S Masoud Hosseini

Mohammad Reza Safaei

Patrice Estellé
email: patrice.estelle@univ-rennes1.fr

S Hadi Jafarnia

Heat transfer of water based carbon nanotube nanofluids in the shell and tube cooling heat exchangers of the gasoline product of the Residue Fluid Catalytic Cracking unit

Keywords: Tube and shell heat exchanger, Carbon nanotube water-based nanofluids, Concentration, Mass flow rate, Thermal performance ___________________________________________________________________________

Heat transfer of water-based carbon nanotube nanofluids in the shell and tube cooling heat exchangers

of the gasoline product of the residue fluid catalytic cracking unit

Nomenclature flow area of tube side (m 2 ) total heat transfer area of tube outside (m 2 ) area of cross flow (m 2 ) minimum specific heat (J/kg.K) fluid specific heat (J/kg.K) viscosity improvement coefficient inner tube diameter (m) outside tube diameter (m) equivalent diameter (m) convection heat transfer coefficient for shell side fluid (W/m 2 .K) convection heat transfer coefficient for nanofluid (W/m 2 .K) convection heat transfer coefficient for hot fluid (W/m 2 .K) thermal conduction for nanofluid (W/m.K) thermal conduction for shell side fluid (W/m.K) thermal conduction for tube (W/m.K) nanofluid mass flow rate (kg/s) shell side fluid mass flow rate (kg/s) Nusselt number of nanofluid Prandtl number of nanofluid Prandtl number of shell side friction factor heat transfer rate (kW) hot fluid outlet temperature ( o C) cold fluid outlet temperature ( o C) shell side fluid Reynolds number nanofluid Reynolds number total heat transfer coefficient(W/m 2 .K) nanofluid viscosity (mPa.s) base fluid viscosity (mPa.s) shell side fluid viscosity (mPa.s) nanoparticle volume fraction log mean temperature difference ( o C) effectiveness of heat exchanger

Introduction

Nanofluids are engineered colloidal suspensions of nanoparticles < 100 nm in a base fluid, which have recently been proposed as new generation of heat transfer fluids. Various nanoparticles have been selected to produce nanofluids, including metals [START_REF] Ozsoy | Thermal performance of a thermosyphon heat pipe evacuated tube solar collector using silver-water nanofluid for commercial applications[END_REF][START_REF] Nakhchi | Cu-water nanofluid flow and heat transfer in a heat exchanger tube equipped with cross-cut twisted tape[END_REF], metal oxides [START_REF] Budak Ziyadanogullari | Thermal performance enhancement of flat-plate solar collectors by means of three different nanofluids[END_REF][START_REF] Kim | Experimental investigation of heat transfer coefficient with Al 2 O 3 nanofluid in small diameter tubes[END_REF] and nonmetals [START_REF] Azwadi | A review on the use of carbon nanotubes nanofluid for energy harvesting system[END_REF][START_REF] Hu | Effect of nanoparticle size and concentration on boiling performance of SiO 2 nanofluid[END_REF]. These suspensions exhibit noticeably higher thermal conductivity than the pure liquid [START_REF] Sarviya | Review on Thermal Conductivity of Nanofluids[END_REF] which could improve heat transfer in heat exchangers [START_REF] Bahiraei | Recent research contributions concerning use of nanofluids in heat exchangers: A critical review[END_REF][START_REF] Kumar | Application of nanofluids in plate heat exchanger: A review[END_REF] since low thermal conductivity of the process fluids like water, ethylene glycol and industrial oils [START_REF] Ozsoy | Thermal performance of a thermosyphon heat pipe evacuated tube solar collector using silver-water nanofluid for commercial applications[END_REF][START_REF] Nakhchi | Cu-water nanofluid flow and heat transfer in a heat exchanger tube equipped with cross-cut twisted tape[END_REF][START_REF] Valtteri Mikkola | Thermal properties and convective heat transfer of phase changing paraffin nanofluids[END_REF][START_REF] Sani | Graphite/diamond ethylene glycolnanofluids for solar energy applications[END_REF] prevents high effectiveness of heat exchangers through making their heat transfer capability limited. Therefore, in most applications in which cooling or heating processes are performed by conventional fluids, nanofluids could be used rather than common single phase fluids. For instance, nanofluids can be used in refrigerators, solar heaters, heating and cooling of buildings, radiators of cars, condensing and evaporating systems, oil recovery, medicine drug delivery and any type of liquid based heat exchangers [START_REF] Rashidi | Potentials of porous materials for energy management in heat exchangers -A comprehensive review[END_REF][START_REF] Shamsabadi | Entropy generation analysis for nanofluid flow inside a duct equipped with porous baffles[END_REF][START_REF] Rashidi | Second law of thermodynamics analysis for nanofluid turbulent flow inside a solar heater with the ribbed absorber plate[END_REF][START_REF] Rashidi | Combined effects of nanofluid and transverse twisted-baffles on the flow structures, heat transfer and irreversibilities inside a square duct-A numerical study[END_REF][START_REF] Parizad Laein | Experimental investigation of nanofluid free convection over the vertical and horizontal flat plates with uniform heat flux by PIV[END_REF][START_REF] Maskaniyan | A two-way couple of Eulerian-Lagrangian model for particle transport with different sizes in an obstructed channel[END_REF][START_REF] Rashidi | Applications of nanofluids in condensing and evaporating systems A review[END_REF][START_REF] Rashidi | Combination of nanofluid and inserts for heat transfer enhancement[END_REF][START_REF] Omid Mahian | Recent advances in modeling and simulation of nanofluid flows-Part I: Fundamentals and theory[END_REF] Heat exchangers are important devices in chemical processes and industries in the field of energy and heat transfer. One of heat exchangers types is shell and tube one which is used in oil and gas industries, for example.

In recent years, the use of nanofluids in the heat exchangers, like shell and tube type, has thoroughly been recognized as a promising possibility in order to enhance heat transfer performance and save energy in various processes [START_REF] Rashidi | Energy saving in thermal energy systems using dimpled surface technology -A review on mechanisms and applications[END_REF].

Barzegarian et al. [START_REF] Barzegariana | Thermal performance augmentation using water based Al 2 O 3 -gamma nanofluid in a horizontal shell and tube heat exchanger under forced circulation[END_REF] used Al 2 O 3 -water nanofluids in a shell and tube heat exchanger and evaluated the effect of friction factor, Reynolds number and nanoparticles volume fraction on the heat performance. This work was performed under laminar flow condition. They found that the total heat transfer coefficient and thermal performance factor could be improved by increasing Re and nanoparticles volume fraction. For example, with 0.3 %vol. in Al 2 O 3 nanoparticles, the total heat transfer coefficient and thermal performance factors are increased by 29.8% and 18.9% respectively with a weak increase in the pressure drop.

Likewise, similar nanofluids were investigated by Shahrul et al. [START_REF] Shahrul | Experimental investigation on Al 2 O 3 -W, SiO 2 -W and ZnO-W nanofluids and their application in a shell and tube heat exchanger[END_REF] in a tube and shell heat exchanger. They studied the effect of mass flow rate of both the shell and tube sides. The heat exchanger performance was analyzed and the results were compared with water. These experiments demonstrated that the total heat transfer coefficient increased up to 26% in comparison with water and greatest performance was observed at 7 LPM flow rate.

Hosseini et al. [START_REF] Hosseini | Performance of CNT-water nanofluid as coolant fluid in shell and tube intercooler of a LPG absorber tower[END_REF] studied CNT-water nanofluid with low volume fractions. The performance of an industrial heat exchanger was simulated by heat exchanger design, rating and simulation software in laminar flow regime. They concluded that with increase of CNT concentration, heat transfer properties would be increased so that the total heat coefficient is 14.5% higher and heat rate reached 10.3% for the highest volume concentration. Furthermore, increasing CNT concentration caused reduction of temperature of the outlet of the shell side fluid compared with water. It was demonstrated that increasing mass flow rate could increase heat transfer. Increase in pressure drop and pumping power was reported to be small and negligible.

Al-Abdali et al. [START_REF] Al-Abdali | Investigation of heat transfer and friction factor of Al 2 O 3 nanofluid inside shell and tube heat exchanger[END_REF] also conducted an experimental investigation on water based Al 2 O 3 nanofluid to determine the evolution of the friction factor and Nusselt number in a tube and shell heat exchanger. The tubes were finned and without fin. The Reynolds number were changed from 3,000 to 10,500, also the nanofluid volume concentration was 0.1 %, 0.2 %, and 0.3 %. It was observed that Nusselt number and friction factor increased with nanofluid concentration. Increasing Re (increasing turbulence) led to higher Nusselt number. At highest nanofluid concentration (0.3 %), the Nusselt number increased by 25.6% for tube without fin.

For finned tube, Nusselt number increased by 11.8% for highest Reynolds number (Re = 10500) and highest nanofluid concentration of 0.3 %. Aghabozorg et al. [START_REF] Mohammad Hossein Aghabozorg | Experimental investigation of heat transfer enhancement of Fe 2 O 3 -CNT/ water magnetic nanofluids under laminar, transient and turbulent flow inside a horizontal shell and tube heat exchanger[END_REF] used nanofluid made of distilled water and Fe 2 O 3 -CNT magnetic nanoparticle in a horizontally positioned tube and shell heat exchanger. They carried out test under various flow conditions (laminar, transient and turbulent flows) and three different heat fluxes. The results showed that increasing ϕ and T results in higher convection heat transfer coefficient. The heat transfer coefficient of the nanofluid was higher than base fluid. At ϕ =0.1%, heat transfer increased by 13.54% and 27.69% for laminar and turbulent flows. For ϕ = 0.2%, the heat transfer coefficient increased by 34.02% and 37.50% in comparison with distilled water for laminar and turbulent flows condition respectively.

Many works performed on heat transfer of nanofluids in various types of heat exchangers are experimental. Although experimental studies are worthwhile approaches to research, they go with some disadvantages such as determining difficultly contribution of physical phenomena to the system as well as the possible high expense of experiments that are obstacles for doing experimental studies because it can require a large amount of sample or specific technical developments. Thus, modeling and simulation are going great on their ways to becoming beneficial and wonder alternatives rather than experiments [START_REF] Omid Mahian | Recent advances in modeling and simulation of nanofluid flows-Part II: Applications[END_REF] as not only make lower costs but also can give highly detailed data and results on the system studied [START_REF] Omid Mahian | Recent advances in modeling and simulation of nanofluid flows-Part II: Applications[END_REF]. However, this requires using appropriate models for thermophysical properties or reliable experimental data.

In the current study, simulation of the Residue Fluid Catalytic Cracking unit (RFCC) gasoline product shell and tube cooler was carried out by using CNT-water nanofluids as coolant in low nanoparticle volume fractions. The simulation was performed considering real experimental data for nanofluids as done in previous works with different configurations such as square cavity [START_REF] Estellé | Natural convection of CNT water based nanofluids in a differentially heated square cavity[END_REF], pipe [START_REF] Minea | Numerical study on CNT nanofluids behavior in laminar pipe flow[END_REF] and microchannel heat sink [START_REF] Mohd-Ghazali | Thermal and hydrodynamic performance of a microchannel heat sink with carbon nanotubes nanofluids: Effect of concentration and channel section[END_REF]. The heat transfer performance of the RFCC was analyzed considering the influence of nanofluid concentrations and fluid mass flow rate.

2-Problem definition

One of oil refining units (in Arak Petroleum Refinery, Iran) is called RFCC (residue fluidized catalytic cracking). There is a debutanizer tower in this unit where gasoline and LPG, produced through RFCC process, are separated from each other in this tower as LPG is up flow and gasoline is bottom one. Outlet gasoline product from debutanizer column bottom, after passing through six air coolers, flows through the shell sides of two shell and tube heat exchangers in order to be more cooled by cooling water flows in tubes. Figure 1 illustrates this real shell and tube heat exchangers that is investigated in this study.

A branch of the cooled gasoline is utilized as the absorber fluid in a LPG absorption column (is called primary absorber). In this tower, LPG of the process gas which contents fuel gas (Methane and Ethane) as well is absorbed by the mentioned cooled gasoline as absorber fluid in order to be separated from the fuel gas. Therefore, the gasoline temperature is a very significant item since, generally, temperature is a vital factor in absorption process and this justifies the use of the mentioned heat exchangers for regulating (decreasing) the temperature of the gasoline.

During the warm seasons of year, the air coolers could not be entirely capable to work on total duty. Likewise, temperature of the cooling water supply flowing in the tubes increases because of high ambient temperature and being the utility power plant unable to supply the cooling water with the regulated temperature (usually 25 0 C). Therefore, cooling performance efficiency in the shell and tube heat exchanger decreases. Consequently, outlet temperature of shell side gasoline rises, leading to lower absorption efficiency in the primary absorber column, causing loss of LPG through top flow. Enhancing the thermal properties of the heat transfer fluids is one of the methods for solving this problem. With this goal, the use of water based nanofluid containing carbon nanotubes in the heat exchanger has been analyzed numerically.

Modelling

The calculations for heat exchangers design and simulation are hugely difficult and complicated. For instance, to design a heat exchanger, many initial guesses must be considered which make calculations really irritating and boring as well as they increase probability of error in results. But, by using the software, all these calculations are performed by computer with noticeably faster pace just through applying the operational condition and the properties of working fluids as well as much more precise results would be available. ASPEN HTFS+ 7.3 is useful software to simulate, design and evaluate the performance of the various types of heat exchangers such as shell and tube, plate, kettle and air cooler heat exchanger. This software is more comprehensive in data bank and the applications and features than the others like B-JAC software. HTFS+ has four calculation modes such as Design, Checking, Simulation and Maximum Fouling.

Among the mentioned calculation modes, simulation mode is here considered to simulate the shell and tube heat exchanger described in Fig. 1. Within this mode, the heat exchanger specifications, the composition and operational/process condition of the shell side and tube side fluids and the cooling fluid thermophysical properties are entered into the software as inlet data. Then, after running the software, it makes the outlet fluids process condition and heat transfer rate available. Water based CNT nanofluids were introduced as cooling fluids. It is mentionable that thermophysical properties of the shell side fluid (gasoline) are calculated by the software through the composition and process condition. For thermophysical properties of the nanofluid as tube side cooling fluid, the data from Halelfadl et al. [START_REF] Halelfadl | Efficiency of carbon nanotubes water based nanofuids as coolants[END_REF] were used in order to supply input data for the simulation software. Volume fractions of the nanofluids were 0.0055%, 0.055%, 0.111% and 0.278%. More details about nanofluids characterization and properties evaluation can be found elsewhere [START_REF] Halelfadl | Efficiency of carbon nanotubes water based nanofuids as coolants[END_REF]. Figure 2 expresses the influence of temperature and CNT loading effects on the thermophysical properties of presently used CNT nanofluids [START_REF] Halelfadl | Efficiency of carbon nanotubes water based nanofuids as coolants[END_REF]. Because of turbulent flow involved within the tube of the heat exchanger, viscosity data of the CNT-water nanofluids used and reported in Figure 2 are for high shear rate. All other data necessary to the simulation process are gathered in Tables 1 and2. Table 1 presents gasoline composition. Likewise, Table 2 contains information about heat exchanger geometry. Figures 3(a) [32] and 3 (b) (given from the software) also demonstrate schematically some geometry specifications as well as the flow parameters.

At first, the simulation was performed with water as cooling fluid to ensure validity of the results. After that, nanofluid simulations were carried out. (1) (

Results and discussion

Influence of the nanoparticle concentration on thermal performance of tube and shell sides at constant mass flow rates

) 5
Increase of Nusselt numbers for 0.0055%, 0.055%, 0.111% and 0.278% volume fractions are about 30%, 32%, 20% and 2.3%, respectively, related to the water. Therefore, increment of the Nusselt number for 0.055% volume fraction is highest related to the others. Increasing the Nusselt number of the fluids to 0.055% CNT volume concentration and increasing thermal conductivity through increasing ϕ results in higher total heat transfer coefficient. 0.055% CNT volume concentration possesses maximum total heat transfer coefficient related to others about 650.7 W/m 2 K. For higher concentrations, the total heat transfer coefficient decreases by reducing Nusselt number (Eq. 7). Heat transfer rate is proportional to total heat transfer coefficient (Eq. 8). Figure 9 shows heat transfer vs CNT concentrations. A maximum heat transfer of about 4133 kW occurs at ϕ = 0.055 vol. % since the total heat transfer coefficient is maximum at this point. The total heat transfer coefficient and heat transfer rate for all the CNT concentrations are higher than for water.

(6) Since maximum heat transfer rate is obtained for 0.055 vol. % CNT nanofluids, the minimum temperature of shell side fluid outlet occurs at ϕ=0.055 as shown in Figure 10. Figure 11 illustrates that pressure drop in tube side, provided by the software, increases with CNT concentration, which is directly linked to the increase in viscosity with higher ϕ, and the effect is more prominent at higher ϕ values which have higher pressure loss as well.

Influence of CNT nanofluid mass flow rate on thermal performance

According to Eq. ( 1), the coolant Reynolds's number is function of the mass flow rate at a constant ϕ. Hence, when the nanofluid mass flow rate is increased, its Reynolds's number rises, too. This explanation has been portrayed in Figure 12. With increment of coolant mass flow rate, Prandtl number also increases for a constant ϕ (Figure 13). It would be understood from Eq. 4 that friction factor has an inverse relation with Reynolds number as friction factor decreases with increase of Reynolds number due to the mass flow rate. This trend has been demonstrated in Figure 14. Figure 15 shows that the variations of the items mentioned above due to rise of the coolant mass flow rate result in the increase of Nusselt number. In other words, the rise of coolant mass flow rate causes increment of the Nusselt number for a constant CNT concentration. As can be seen, ϕ=0.055% possesses the highest Nusselt number. It is clear from Fig. 16 that as the coolant mass flow rate increases, tube side pressure drop increase, too as well as it increases with ϕ. Regarding Eqs. [START_REF] Hu | Effect of nanoparticle size and concentration on boiling performance of SiO 2 nanofluid[END_REF][START_REF] Sarviya | Review on Thermal Conductivity of Nanofluids[END_REF][START_REF] Bahiraei | Recent research contributions concerning use of nanofluids in heat exchangers: A critical review[END_REF], the Nusselt number increase makes the total heat transfer coefficient increase (Fig. 17) for all the concentrations. With increase of the total heat transfer coefficient, finally, rise of heat transfer rate happens (Fig. 18), in particular, for ϕ=0.055% since this loading amount has the maximum total heat transfer coefficient and Nusselt number.

As the heat transfer from the shell side fluid to the tube side cold one, with increase of the heat transfer due to mass flow rate, the outlet temperature of the shell side fluid decreases as it is evidenced in Fig. 19. Reasonably, minimum outlet temperature belongs to 0.055% CNT loading since the heat exchanger has highest heat transfer rate with this cooling nanofluid. Eq. ( 10) [START_REF] Hosseini | Performance of CNT-water nanofluid as coolant fluid in shell and tube intercooler of a LPG absorber tower[END_REF] shows that higher Re results in higher convection heat transfer coefficient, and consequently, higher heat transfer rate (Eqs. 7 and 8). As shown in Figures 21 and22, increasing of shell side mass flow rate results in higher total heat transfer coefficient and heat transfer rate. Nanofluid coolant results in better thermal performance compared to pure water coolant.

( In other words, by using the nanofluid, shell side hot fluid is less heated related to using cooling water. Thus, by utilizing the nanofluid, viscosity of the shell side fluid would be higher than cooling water. Therefore, by using the nanofluid, Reynolds number of the shell side fluid decreases as expressed by Eq. 9. For instance, in Figure 20, the shell side fluid Reynolds reduces when water is replaced by nanofluids especially at ϕ =0.0055 and 0.055%.

As demonstrated by Figure 23, the magnitude of the outlet temperature increase for ϕ=0.055 is lower than for other concentrations since it causes most heat transfer rate.

Conclusion

This research studied the heat performance of an industrial scale shell and tube heat exchanger through software simulation by using CNT-water nanofluids as cooling fluids.

Results illustrated that all analyzed CNT concentrations improved the heat properties such as Nusselt number, total heat transfer coefficient and heat transfer rate and, consequently they enhanced the heat performance of the heat exchanger. This enhancement was also effective to decrease outlet temperature of the shell side hot fluid for all CNT volume concentrations.

Likewise, there was an optimum CNT concentration corresponding to 0.055 vol% of nanoparticles for which the heat properties reached maximum value and thermal performance of the heat exchanger is optimized. The heat performance enhancement was reached also by increasing mass flow rates of both the cooling nanofluid in all concentrations and the hot fluid in comparison with cooling water. It is also mentioned that optimum concentration of 0.055% also kept the best influence on thermal performance of the heat exchanger with increasing mass flow rates of the fluids in both sides.

Fig. 1 .

 1 Fig.1. Real shell and tube cooling heat exchangers of the RFCC gasoline product that have been modelized. (1) Inlet cooling water to tubes, (2) Outlet cooling water from tubes, (3) Inlet gasoline product to shell, (4) Outlet gasoline product from shell

Fig. 2 .

 2 Fig.2. Effects of temperature and CNT volume fraction on the thermophysical properties of nanofluids from[START_REF] Halelfadl | Efficiency of carbon nanotubes water based nanofuids as coolants[END_REF]

Fig. 3a .

 3a Fig.3a. Schematic figure of the heat exchanger[START_REF] Minea | Numerical study on CNT nanofluids behavior in laminar pipe flow[END_REF]

Figure 4

 4 Figure 4 shows the nanofluid Reynolds number Re nf , evaluated from equation (1), in function CNT concentration co s = 81.74 kg/s in tube side. It is observed that Re nf decreases by increasing CNT concentration due to the increase of nanofluid viscosity with the content in nanotubes. Range values of Re nf indicates that the flow is under turbulent regime as expected.

Fig. 4 .Figure 5 Fig. 5 .Figure 6 Fig. 6 .Figure 7 shows

 455667 Fig. 4. Re of coolant as a function of CNT loading

Fig. 7 .Figure 8

 78 Fig. 7. Coolant Nusselt number as a function of CNT loading

Fig. 8 .

 8 Fig. 8. Total heat transfer coefficient as a function of CNT loading

Fig. 9 .

 9 Fig. 9. Heat transfer rate as a function of CNT loading

Fig. 10 .

 10 Fig. 10. Outlet temperature of shell side fluid versus CNT loading

Fig. 11 .

 11 Fig. 11. Coolant pressure drop as a function of CNT loading

  Fig. 12. Effect of on Reynolds number

Fig. 14 Fig. 15 .

 1415 Fig. 14. Effect of on the friction factor

Fig. 16 .FigFig. 18 .Fig. 19 . 4 . 3 .

 16181943 Fig. 16. Coolant pressure drop as a function of

( 9 )Fig. 20 .

 920 Fig. 20. Reynolds number of shell side fluid as a function of

Fig. 21 .Figure 23

 2123 Fig. 21. Total heat transfer coefficient versus

Fig. 23

 23 Fig. 23. Effect of on its Outlet temperature

Table 2 .

 2 Specification of the heat exchanger as well as operational condition of the fluids in shell Side (gasoline) and tube side (the coolants)

	Parameter	Amount/type	Parameter	Amount/type
	Shell inner diameter (mm)	950	Baffle type	Single segmental
	Shell outer diameter (mm)	974	Baffle spacing (center-center) (mm)	310
	Tube number	868	Baffle cut %	27
			Mass flow rate of fluid in shell side
	Tube passes per shell	4	(gasoline) (kg/s)	124.7631
			Mass flow rate of tube side fluid (cooling
	Tube length (mm)	6100	water and the nanofluid) (kg/s)	81.7394
	outer diameter of Tube (mm)	19.05	Shell side fluid Inlet temperature ( 0 C)	55
	Thickness of Tube (mm)	1.65	Tube side fluid Inlet temperature ( 0 C)	29
	Tube pitch (mm)	27.4	Shell side fluid Inlet pressure (bar)	10.3
	Tube pattern	45-Rotated sqr.	Tube side fluid Inlet pressure (bar)	3.9


Oscar Chávez-Talavera +

Joel Haas +

Guillaume Grzych

Anne Tailleux #

Bart Staels
email: bart.staels@pasteur-lille.fr

Bile acid alterations in non-alcoholic fatty liver disease, obesity, insulin resistance and type 2 diabetes: what do the human studies tell?

Keywords: Bile acids, NAFLD, NASH, obesity, insulin resistance, type 2 diabetes, metabolic syndrome

Purpose of review:

To discuss the influence of obesity, insulin resistance, type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD) on bile acid (BA) metabolism and analyze whether these findings reinforce current beliefs about the role of BAs in the pathophysiology of these diseases.

Recent findings: Discordant results on plasma BA alterations in NAFLD patients have been reported.

Obesity, insulin resistance and T2D, common co-morbidities of NAFLD, have been associated with BA changes, but the individual BA species variations differ between studies (summarized in this review), perhaps due to clinico-biological differences between the studied patient populations and the heterogeneity of statistical analyses applied.

Summary:

The regulatory role of BAs in metabolic and cellular homeostasis render BAs attractive candidates as players in the pathophysiology of NAFLD. However, considering the complex relationship between NAFLD, obesity, insulin resistance and T2D, it is difficult to establish clear and independent associations between BA alterations and these individual diseases. Though BA alterations may not drive NAFLD progression, signaling pathways activated by BAs remain potent therapeutic targets for its treatment. Further studies with appropriate matching or adjustment for potential confounding factors are necessary to determine which pathophysiological conditions drive the alterations in BA metabolism.

1. BA changes have been associated with obesity, insulin resistance and T2D, common comorbidities of NAFLD.

2. Discordant results on plasma BA alterations in NAFLD patients have been reported.

3. The intricate relationship between NAFLD, obesity, insulin resistance and T2D renders difficult the establishment of clear and independent associations between BA alterations and these individual diseases.

4. Further studies with appropriate matching or adjustment for potential confounding factors are necessary to determine which of these diseases drive the alterations in BA metabolism in NAFLD.

Introduction

The increasing global prevalence of the metabolic syndrome (MetS), which groups obesity, hyperglycemia, dyslipidaemia and hypertension, is a major worldwide public health problem. Nonalcoholic fatty liver disease (NAFLD) is often considered the hepatic manifestation of MetS, and is closely related to many of its features. NAFLD comprises a hepatic spectrum ranging from simple hepatic steatosis or non-alcoholic fatty liver (NAFL), characterized by abnormal triglyceride accumulation in hepatocytes, which can progress to non-alcoholic steatohepatitis (NASH). While NAFL is generally considered benign, NASH combines NAFL with elements of hepatic tissue injury including evidence of inflammation and hepatocyte ballooning with or without fibrosis. NAFLD is an independent risk factor for cirrhosis, hepatocellular carcinoma, cardiovascular disease and mortality.

Importantly, NAFLD is strongly and bidirectionally associated with obesity, insulin resistance (IR) and type 2 diabetes (T2D) [START_REF] Diehl | Cause, Pathogenesis, and Treatment of Nonalcoholic Steatohepatitis[END_REF][2][3].

There are several unmet research needs in the field of NAFLD. The natural history of NAFLD is not entirely understood, and no pharmacological therapies exist for its treatment. For example, NAFL can be diagnosed with non-invasive imaging techniques, but NASH diagnosis currently requires liver biopsy for histological evaluation, an intervention not devoid of risk, and highly susceptible to interobserver variations [4]. It is thus urgent to find circulating biomarkers to better identify those patients to be submitted to biopsy for NASH screening and monitoring NAFLD progression and staging for assessment of treatment efficacy. Recently, BAs have emerged as potential candidates, and new emerging therapies for NAFLD target BA signaling pathways. Moreover, some evidence suggests that BA alterations could be associated with NAFLD.

Bile acid physiology

BAs are cholesterol-derived molecules synthesized exclusively in hepatocytes via two pathways. The classical pathway produces the majority of BAs. It is initiated by cytochrome P450 (CYP) cholesterol 7α-hydroxylase (CYP7A1), whose activity correlates with plasma levels of 7α-hydroxy-4-cholesten-3one (C4). The alternative pathway, initiated by CYP 27α-hydroxylase (CYP27A1), synthesizes the remaining minor BA fraction. These pathways produce the primary BAs cholic acid (CA), chenodeoxycholic acid (CDCA) and hyocholic acid (HCA) in humans. Notably, CA is a 12αhydroxylated-BA, synthetized by the CYP 12α-hydroxylase (CYP8B1), which is indirectly regulated by insulin signalling via FoxO1. Thus, the 12α-hydroxylated:non-12α-hydroxylated BA ratio reflects the activity of CYP8B1, and is a marker of hepatic insulin sensitivity of the BA synthesis pathway. Upon synthesis, BAs are conjugated to glycine or taurine (the proportion being essentially determined by dietary intake), secreted into bile and released in the duodenum post-prandially to facilitate dietary fat solubilization and absorption. In the gut, microbiota deconjugate and transform primary BAs into secondary BAs: CA into DCA (also a 12α-OH BA), CDCA into UDCA and LCA, and HCA into HDCA. ~95% of BAs are recaptured in the ileum and return to the liver via the portal vein to be re-conjugated and re-secreted into bile. A minor fraction of portal BAs escape hepatic reuptake and reach the systemic circulation, hence potentially allowing signaling actions in peripheral organs [5]. However, it should be noted that circulating plasma BAs do not necessarily reflect the composition of the portal, intra-hepatic, biliary or intestinal BA pools.

Besides their role in dietary lipid solubilization, BAs are natural ligands of the Farnesoid X receptor (FXR) and the Takeda G protein coupled receptor (TGR5), through which BAs regulate their own synthesis, as well as glucose, lipid and energy homeostasis, inflammation, hepatic fibrosis and modulate reparative activity (reviewed in [5]). Importantly, not all BAs activate FXR (CDCA>DCA>CA>LCA) and TGR5 (LCA>DCA>CDCA>CA) with the same affinity nor potency.

Hence, qualitative alterations of the BA pool composition, in addition to quantitative changes in total BAs, could modulate the activity of their receptors and hence impact metabolism.

BA-FXR signaling in enterocytes stimulates the secretion of Fibroblast Growth Factor 19 (FGF19) into portal venous blood, which then activates FGFR4/Klotho in the liver. Through this mechanism, FGF19 suppresses CYP7A1, thereby decreasing BA synthesis via the classical pathway, and also regulates hepatic carbohydrate and lipid metabolism. Interestingly, plasma FGF19 (a biomarker of intestinal FXR activation) is decreased in the metabolic syndrome, suggesting that it could be implicated in the pathogenesis of NAFLD [6,7]. Considering the many interactions between diet, insulin signaling and BA metabolism, it appears logical that alterations in circulating BAs could be markers of, or even actors in, the pathophysiology of the metabolic processes that they modulate.

Bile acids in obesity, insulin resistance and type 2 diabetes

The effect of obesity on BA metabolism is not entirely clear. BMI has been reported to positively correlate with fasting BAs A parameter confounding these studies may be related to differences in the level of insulin resistance among the studied patient populations. Studies analyzing BA changes in insulin resistant, but not diabetic, patients have reported higher fasting total and 12α-OH BAs [16]. Mechanistic studies in insulin-resistant mice suggest that impaired insulin-mediated repression of FoxO1 results in higher 12α-hydroxylase CYP8B1 expression [START_REF] Haeusler | Impaired generation of 12-hydroxylated bile acids links hepatic insulin signaling with dyslipidemia[END_REF]. Moreover, insulin resistance was associated with increased total BA concentrations [START_REF] Sun | Insulin Resistance is Associated With Total Bile Acid Level in Type 2 Diabetic and Nondiabetic Population: A Cross-Sectional Study[END_REF][START_REF] Ginos | Circulating bile acids in healthy adults respond differently to a dietary pattern characterized by whole grains, legumes and fruits and vegetables compared to a diet high in refined grains and added sugars: A randomized, controlled, crossover feeding study[END_REF], fasting tauro-conjugated BAs [START_REF] Wewalka | Fasting serum taurine-conjugated bile acids are elevated in type 2 diabetes and do not change with intensification of insulin[END_REF], CDCA, CA, DCA [13] and GCDCA [START_REF] Kimberly | Metabolite profiling identifies anandamide as a biomarker of nonalcoholic steatohepatitis[END_REF]. Some studies in overtly T2D patients have reported no changes in fasting [9,[START_REF] Vincent | Higher circulating bile acid concentrations in obese patients with type 2 diabetes[END_REF] or postprandial [9,[START_REF] Jørgensen | Improvements in glucose metabolism early after gastric bypass surgery are not explained by increases in total bile acids and fibroblast growth factor 19 concentrations[END_REF] BAs compared to controls, whereas other studies have reported either increased fasting [7,16,24] and postprandial [START_REF] Sonne | Postprandial Plasma Concentrations of Individual Bile Acids and FGF-19 in Patients With Type 2 Diabetes[END_REF] total BA concentrations, increased fasting DCA [9,13,25], TCDCA, TDCA and TUDCA [START_REF] Wewalka | Fasting serum taurine-conjugated bile acids are elevated in type 2 diabetes and do not change with intensification of insulin[END_REF], or decreased CA and HCA [START_REF] Suhre | Metabolic footprint of diabetes: a multiplatform metabolomics study in an epidemiological setting[END_REF]. BA levels were not modified by intensive insulin treatment in diabetic patients [START_REF] Wewalka | Fasting serum taurine-conjugated bile acids are elevated in type 2 diabetes and do not change with intensification of insulin[END_REF].

The mechanisms underlying the quantitative and qualitative modifications in BAs in the metabolic syndrome are not fully elucidated. Besides the previously described alterations of the insulin receptor-Akt-FoxO1 signaling pathway impacting BA synthesis in insulin resistance, dysbiosis (occuring in metabolic disorders) could modify BA de-conjugation, secondary BA synthesis and modulate the BA pool composition [5]. Another mechanism implies the entero-hepatic crosstalk via intestinally FXRinduced FGF19. Indeed, FGF19 levels correlate positively with total BA concentrations [10,24] and negatively with plasma C4 [10,[START_REF] Lundåsen | Circulating intestinal fibroblast growth factor 19 has a pronounced diurnal variation and modulates hepatic bile acid synthesis in man[END_REF]. Interestingly, FGF19 is lower in T2D and obese patients and correlates negatively with BMI [10,27] and HbA1c [START_REF] Barutcuoglu | Fibroblast growth factor-19 levels in type 2 diabetic patients with metabolic syndrome[END_REF]. However, these changes in FGF19 in T2D patients [9,[START_REF] Sonne | Postprandial Plasma Concentrations of Individual Bile Acids and FGF-19 in Patients With Type 2 Diabetes[END_REF] or its correlation with MetS components [START_REF] Wewalka | Fasting serum taurine-conjugated bile acids are elevated in type 2 diabetes and do not change with intensification of insulin[END_REF] are not universally observed. Importantly, differences in control populations and the degree of IR or T2D severity are potential confounding factors between these studies and are not always well reported nor well characterized.

In conclusion, although not all reported data are entirely consistent, it is clear that BA metabolism alterations occur in obese and/or insulin resistant humans (summarized in Table 1). However, it remains undetermined whether BAs are innocent bystanders or if they participate to the pathophysiology of these diseases.

Bile acids and NAFLD

Given that BA accumulation in hepatocytes is cytotoxic in intrahepatic cholestatic liver diseases; it is conceivable that BAs could be altered in NAFLD also and that their accumulation in NASH patients could favor progression of the disease. Furthermore, hepatic necro-inflammatory lesions in NAFLD may alter the anatomy of liver zonation. Since the liver is the sole site of BA synthesis and since BA synthesis is zonated in physiological conditions, altered BA metabolism could occur in a setting of pathologically altered liver zonation. Indeed, treatment of NASH with the FXR agonist obeticholic acid [START_REF] Neuschwander-Tetri | Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebocontrolled trial[END_REF] or with the FGF19 analog NMG282 [START_REF] Harrison | NGM282 for treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial[END_REF] improved several NAFLD histological features.

Therefore, several groups have studied whether NAFLD patients present BA profile alterations (summarized in Table 2).

Fasting plasma BAs were reported to be higher in NASH patients due to increased primary [START_REF] Puri | The presence and severity of nonalcoholic steatohepatitis is associated with specific changes in circulating bile acids[END_REF] and conjugated BA species [START_REF] Puri | The presence and severity of nonalcoholic steatohepatitis is associated with specific changes in circulating bile acids[END_REF][START_REF] Kalhan | Plasma metabolomic profile in nonalcoholic fatty liver disease[END_REF][START_REF] Ferslew | Altered Bile Acid Metabolome in Patients with Nonalcoholic Steatohepatitis[END_REF]. Similar changes were also observed in NAFL patients [START_REF] Kalhan | Plasma metabolomic profile in nonalcoholic fatty liver disease[END_REF]. Moreover, histological lesions of NASH have been associated with BA alterations (i.e. associations of high plasma GCA [START_REF] Puri | The presence and severity of nonalcoholic steatohepatitis is associated with specific changes in circulating bile acids[END_REF] or CA [START_REF] Caussy | Serum bile acid patterns are associated with the presence of NAFLD in twins, and dose-dependent changes with increase in fibrosis stage in patients with biopsy-proven NAFLD[END_REF] concentrations with lobular inflammation, low TUDCA and high TLCA concentrations with portal inflammation [START_REF] Puri | The presence and severity of nonalcoholic steatohepatitis is associated with specific changes in circulating bile acids[END_REF], high CA, CDCA [START_REF] Caussy | Serum bile acid patterns are associated with the presence of NAFLD in twins, and dose-dependent changes with increase in fibrosis stage in patients with biopsy-proven NAFLD[END_REF], GCA, TCA, GCDCA, DCA and GLCA [START_REF] Puri | The presence and severity of nonalcoholic steatohepatitis is associated with specific changes in circulating bile acids[END_REF] concentrations with hepatocyte ballooning have been reported, as well as elevated total BAs [START_REF] Bechmann | Free fatty acids repress small heterodimer partner (SHP) activation and adiponectin counteracts bile acid-induced liver injury in superobese patients with nonalcoholic steatohepatitis[END_REF], CA, CDCA [START_REF] Caussy | Serum bile acid patterns are associated with the presence of NAFLD in twins, and dose-dependent changes with increase in fibrosis stage in patients with biopsy-proven NAFLD[END_REF], and both increased [START_REF] Puri | The presence and severity of nonalcoholic steatohepatitis is associated with specific changes in circulating bile acids[END_REF] or decreased [START_REF] Caussy | Serum bile acid patterns are associated with the presence of NAFLD in twins, and dose-dependent changes with increase in fibrosis stage in patients with biopsy-proven NAFLD[END_REF] conjugated CA concentrations have been associated with high NAFLD activity score (NAS)). Additionally, increased postprandial total BAs have been reported in plasma and in urine [START_REF] Ferslew | Altered Bile Acid Metabolome in Patients with Nonalcoholic Steatohepatitis[END_REF], as well as increased fecal BA loss, which positively correlated with NAS and associated with decreased proportions of the gut microbiota phylum Bacteroidetes [START_REF] Mouzaki | Bile Acids and Dysbiosis in Non-Alcoholic Fatty Liver Disease[END_REF]. Furthermore, hepatic tissue-extracted BAs were reported to be altered in NASH and NAFL patients resulting in qualitative changes in hepatic BA content, although inconsistent results were obtained between both studies [START_REF] Lake | Decreased hepatotoxic bile acid composition and altered synthesis in progressive human nonalcoholic fatty liver disease[END_REF][START_REF] Aranha | Bile acid levels are increased the liver of patients with steatohepatitis[END_REF]. Such results should be taken with caution, since BAs were extracted from whole hepatic tissue, preventing discrimination between blood, biliary or intrahepatocyte BA concentrations.

The expression of hepatic BA metabolism genes has also been studied in livers from NASH patients.

Both increased [START_REF] Jiao | Suppressed hepatic bile acid signalling despite elevated production of primary and secondary bile acids in NAFLD[END_REF] and decreased [START_REF] Lake | Decreased hepatotoxic bile acid composition and altered synthesis in progressive human nonalcoholic fatty liver disease[END_REF] CYP27A1 mRNA levels were reported, in addition to increased CYP7B1 gene and protein levels [START_REF] Lake | Decreased hepatotoxic bile acid composition and altered synthesis in progressive human nonalcoholic fatty liver disease[END_REF]. These results suggest possible modifications in the alternative BA synthesis pathway. Furthermore, increased expression of the gene encoding CYP7A1 [START_REF] Puri | The presence and severity of nonalcoholic steatohepatitis is associated with specific changes in circulating bile acids[END_REF][START_REF] Jiao | Suppressed hepatic bile acid signalling despite elevated production of primary and secondary bile acids in NAFLD[END_REF][START_REF] Legry | Bile acid alterations are associated with insulin resistance, but not with NASH in obese subjects[END_REF] suggests that the classical BA synthesis pathway may also be activated. FGF19 levels, which regulate bile acid synthesis, have been reported as decreased [START_REF] Jiao | Suppressed hepatic bile acid signalling despite elevated production of primary and secondary bile acids in NAFLD[END_REF] or unchanged [START_REF] Puri | The presence and severity of nonalcoholic steatohepatitis is associated with specific changes in circulating bile acids[END_REF] in NASH patients. Plasma C4 levels are, however, unchanged in NASH patients vs controls [START_REF] Puri | The presence and severity of nonalcoholic steatohepatitis is associated with specific changes in circulating bile acids[END_REF][START_REF] Bechmann | Free fatty acids repress small heterodimer partner (SHP) activation and adiponectin counteracts bile acid-induced liver injury in superobese patients with nonalcoholic steatohepatitis[END_REF][START_REF] Legry | Bile acid alterations are associated with insulin resistance, but not with NASH in obese subjects[END_REF]. A summary of the hepatic gene expression changes reported in NASH patients is provided in Table 2.

We recently compared BA metabolism parameters in NASH patients matched for BMI-and IR with obese individuals without NASH. No qualitative or quantitative differences in fasting plasma BAs was found in NASH patients, with only GCA weakly correlating with steatosis (r=0.29, p=0.03). However, re-analysis by severity of IR revealed a tendency towards previously reported associations in fasting plasma BAs (Table 1). These findings suggest that BA metabolism correlates with the metabolic comorbidities of NAFLD, rather than with the histopathological parameters of NASH itself [START_REF] Legry | Bile acid alterations are associated with insulin resistance, but not with NASH in obese subjects[END_REF]. It will be important in future studies to carefully assess NASH independently of common co-morbidities to determine which changes, if any, in BA metabolism are specifically related to histological changes in NASH.

Are BA changes associated with NAFLD independently from obesity, IR and T2D?

Assessment of the clinico-biological status of the studied populations appears essential to understand discordant results and allow their appropriate interpretation. In studies lacking information on the nutritional status [START_REF] Bechmann | Free fatty acids repress small heterodimer partner (SHP) activation and adiponectin counteracts bile acid-induced liver injury in superobese patients with nonalcoholic steatohepatitis[END_REF][START_REF] Jiao | Suppressed hepatic bile acid signalling despite elevated production of primary and secondary bile acids in NAFLD[END_REF][START_REF] Dasarathy | Elevated hepatic fatty acid oxidation, high plasma fibroblast growth factor 21, and fasting bile acids in nonalcoholic steatohepatitis[END_REF] and biochemical markers of glucose metabolism as fasting plasma glycaemia, HOMA-IR or HbA1c [START_REF] Puri | The presence and severity of nonalcoholic steatohepatitis is associated with specific changes in circulating bile acids[END_REF][START_REF] Caussy | Serum bile acid patterns are associated with the presence of NAFLD in twins, and dose-dependent changes with increase in fibrosis stage in patients with biopsy-proven NAFLD[END_REF][START_REF] Bechmann | Free fatty acids repress small heterodimer partner (SHP) activation and adiponectin counteracts bile acid-induced liver injury in superobese patients with nonalcoholic steatohepatitis[END_REF][START_REF] Jiao | Suppressed hepatic bile acid signalling despite elevated production of primary and secondary bile acids in NAFLD[END_REF][START_REF] Dasarathy | Elevated hepatic fatty acid oxidation, high plasma fibroblast growth factor 21, and fasting bile acids in nonalcoholic steatohepatitis[END_REF], it cannot be excluded that differences between the compared groups, other than histological parameters of NAFLD, influence the interpretation of the results. Many studies that provided the clinico-biological characteristics of the study groups are flawed by the comparison of NASH or NAFL patients with control groups presenting significantly lower BMI [START_REF] Puri | The presence and severity of nonalcoholic steatohepatitis is associated with specific changes in circulating bile acids[END_REF][START_REF] Kalhan | Plasma metabolomic profile in nonalcoholic fatty liver disease[END_REF][START_REF] Ferslew | Altered Bile Acid Metabolome in Patients with Nonalcoholic Steatohepatitis[END_REF][START_REF] Bechmann | Free fatty acids repress small heterodimer partner (SHP) activation and adiponectin counteracts bile acid-induced liver injury in superobese patients with nonalcoholic steatohepatitis[END_REF][START_REF] Jiao | Suppressed hepatic bile acid signalling despite elevated production of primary and secondary bile acids in NAFLD[END_REF], Hb1A1c [START_REF] Bechmann | Free fatty acids repress small heterodimer partner (SHP) activation and adiponectin counteracts bile acid-induced liver injury in superobese patients with nonalcoholic steatohepatitis[END_REF], insulin resistance or fasting glycaemia [START_REF] Kalhan | Plasma metabolomic profile in nonalcoholic fatty liver disease[END_REF][START_REF] Ferslew | Altered Bile Acid Metabolome in Patients with Nonalcoholic Steatohepatitis[END_REF]. As discussed above, these metabolic co-morbidities of NAFLD are correlated with BA alterations. It is thus difficult to conclude whether BA alterations are associated per se with NAFLD, or with the associated insulin resistance. Appropriate statistical adjustment or patient matching could help to determine whether the associations are independent from potential confounding factors.

Conclusion

Though BA signaling targets are attractive candidates for the treatment of NAFLD, it remains undetermined whether BAs are a driving force in the pathogenesis and progression of NAFLD or just innocuous bystanders. The current literature does not clearly support a causal role. Moreover, the large inter-individual variation and diurnal BA changes in peripheral blood suggest that they are likely unsuitable as biomarkers for the diagnosis or leading to the decision of biopsy taking in NAFLD patients. However, this does not exclude that targeting BA signaling remains an attractive therapeutic target for NASH treatment. Further clinical studies assessing plasma BA profiles should carefully consider matching BMI and IR profiles across controls, NAFL and NASH patients in order to more clearly assess the connection between alterations in BA metabolism and these parameters of the metabolic syndrome.

  [8], but negatively with postprandial BAs[9]. Other studies have reported either no changes[10][11][12] or increased concentrations of CA[13] in fasting plasma BAs, and no changes [10] or decreased glyco-conjugated BAs[11] in postprandial plasma of obese individuals.There is also evidence that the normal meal-induced BA increase in plasma BA is suppressed with obesity[12,14]. Similarly, insulin infusion during an euglycemic hyperinsulinemic clamp decreased serum BAs in lean but not in obese patients[12]. Fasting plasma C4 levels were higher in obese subjects in two different studies[12,15], suggesting increased BA biosynthesis. Expression of the canalicular (BSEP) and sinusoidal (NTCP) BA transporter mRNA levels were negatively correlated with BMI[12]. Although there is a large heterogeneity between the reported results, possibly due to the known large inter-and intra-individual variability in BAs and the diurnal variations of BAs in humans [15], overall fasting plasma BAs appear elevated, but the post-prandial increase is lower in obese individuals.

  2. Haas JT, Francque S, Staels B. Pathophysiology and Mechanisms of Nonalcoholic Fatty Liver Disease. Annu Rev Physiol. 2016;78:181-205. * This review summarizes basics of the pathophysiology of NAFLD. 3. Younossi Z, Henry L. Contribution of Alcoholic and Nonalcoholic Fatty Liver Disease to the Burden of Liver-Related Morbidity and Mortality. Gastroenterology. 2016; 150(8):1778-85. 4. Younossi ZM, Loomba R, Anstee QM, et al. Diagnostic modalities for nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and associated fibrosis. Hepatol Baltim Md. 2018; 68(1):349-60. * This review presents a critical overview of the currently available diagnostic techniques for NAFLD. 5. Chávez-Talavera O, Tailleux A, Lefebvre P, Staels B. Bile acid control of metabolism and inflammation in obesity, type 2 diabetes, dyslipidemia and NAFLD. Gastroenterology. 2017; 152(7):1679-1694.e3. * This review describes the role of BAs in the regulation of metabolism in physiology and in the metabolic syndrome. 6. Fang Q, Li H, Song Q, et al. Serum fibroblast growth factor 19 levels are decreased in Chinese subjects with impaired fasting glucose and inversely associated with fasting plasma glucose levels. Diabetes Care. 2013; 36(9):2810-4. 7. Gerhard GS, Styer AM, Wood GC, et al. A role for fibroblast growth factor 19 and bile acids in diabetes remission after Roux-en-Y gastric bypass. Diabetes Care. 2013; 36(7):1859-64. 8. Prinz P, Hofmann T, Ahnis A, et al. Plasma bile acids show a positive correlation with body mass index and are negatively associated with cognitive restraint of eating in obese patients. Front Neurosci. 2015; 9:199. 9. Brufau G, Stellaard F, Prado K, et al. Improved glycemic control with colesevelam treatment in patients with type 2 diabetes is not directly associated with changes in bile acid metabolism. Hepatol Baltim Md. 2010; 52(4):1455-64. 10. Friedrich D, Marschall H-U, Lammert F. Response of fibroblast growth factor 19 and bile acid synthesis after a body weight-adjusted oral fat tolerance test in overweight and obese NAFLD patients: a non-randomized controlled pilot trial. BMC Gastroenterol. 2018; 18(1):76. 11. Glicksman C, Pournaras DJ, Wright M, et al. Postprandial plasma bile acid responses in normal weight and obese subjects. Ann Clin Biochem. 2010; 47(Pt 5):482-4. 12. Haeusler RA, Camastra S, Nannipieri M, et al. Increased Bile Acid Synthesis and Impaired Bile Acid Transport in Human Obesity. J Clin Endocrinol Metab. 2016; 101(5):1935-44. 13. Cariou B, Chetiveaux M, Zaïr Y, et al. Fasting plasma chenodeoxycholic acid and cholic acid concentrations are inversely correlated with insulin sensitivity in adults. Nutr Metab. 2011; 8(1):48. 14. Ahmad NN, Pfalzer A, Kaplan LM. Roux-en-Y gastric bypass normalizes the blunted postprandial bile acid excursion associated with obesity. Int J Obes. 2013 décembre;37(12):1553-9. 15. Steiner C, Othman A, Saely CH, et al. Bile acid metabolites in serum: intraindividual variation and associations with coronary heart disease, metabolic syndrome and diabetes mellitus. PloS One. 2011; 6(11):e25006. ** This article describes inter-and intra-individual BA variations, suggesting that BAs are not good biomarkers for the diagnosis and staging of non-cholestatic metabolic diseases. 16. Haeusler RA, Astiarraga B, Camastra S, et al. Human insulin resistance is associated with increased plasma levels of 12α-hydroxylated bile acids. Diabetes. 2013; 62(12):4184-91. * This article links insulin sensitivity and BA metabolism, showing increased 12a hydroxylation and BA synthesis in obese and insulin resistant patients.

Legend:

  Data extracted from the articles and presented as Means±SD, Means±SEM, Medians[Q1-Q3], Medians[IQR] or Medians(range). *Statistically different from control, $ Statistically different from T2D. Abbreviations: 7α-hydroxy-4-cholesten-3-one (C4), 7α-12α-dihydroxy-4-cholesten-3-one (7,12-diHCO), bile acids (BAs), body mass index (BMI), fasting plasma glycaemia (FPG), glycated hemoglobin (HbA1c), impaired fasting glucose (IFG), impaired glucose tolerance (IGT), insulin sensitivity index (M/I), homeostatic model assessment for insulin resistance (HOMA-IR), metabolic syndrome (MetS), minutes (min), no data (ND), oral fat tolerance test (OFTT).Table 2 Title: Clinical studies assessing BAs in NAFLD Legend: Data extracted from the articles and presented either as Mean±SD, Means±SEM or Median(Range). *NASH statistically different from controls. Abbreviations: bile acids (BAs), body mass index (BMI), fasting plasma glycaemia (FPG) -data reported in sources as mmol/L was transformed to mg/dL by multiplying the reported value by 18-, glycated hemoglobin (HbA1c), homeostatic model assessment for insulin resistance (HOMA-IR), magnetic resonance imaging (MRI) no data (ND).

Table titles and legends.Table 1 .

 1 Title: Clinical studies assessing BAs in obesity, insulin resistance and type 2 diabetes.

Financial support and sponsorship

This work was supported by Agence Nationale pour la Recherche (ANR-10-LABX-46 and ANR-10-INBS-08 ; ProFI project, "Infrastructures Nationales en Biologie et Santé"; "Investissements d'Avenir" call) and by Société Francophone du diabète (SFD). OCT received a PhD fellowship from the French Ministry of Research. BS is a recipient of an Advanced ERC Grant (694717).

Conflicts of interest

None