Farnesoid X Receptor Agonist as a new treatment option for Non-Alcoholic Fatty Liver disease: A Review

Background: Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of fatty liver, characterized by the accumulation of fat in the hepatocytes in the absence of alcohol consumption. The spectrum of this disease ranges from steatosis to hepatitis and finally cirrhosis and hepatocellular carcinoma. NAFLD pathogenesis is not completely understood but various risk factors like obesity, insulin resistance, and metabolic syndromes have been identified. With the rapid increase in obesity and diabetes during the past decade, the incidence of NAFLD is on the rise and is predicted to become the most common indication for liver transplantation in the future.

Context of the study: The treatment option for NAFLD is limited and mainly focuses on risk factor modification like dietary changes and exercise. A major shortcoming of this approach is the lack of adherence and non-compliance over time. Other therapeutic options are available but are limited in number and have questionable efficacy and safety profiles. Thus, new target-oriented therapies are needed.

Results: One such option is using agonists of the farnesoid X receptor (FXR) which are nuclear receptors abundantly expressed in the liver and shown to play a key role in various metabolic pathways such as bile acid, cholesterol, lipid and glucose metabolism.

Main focus and conclusions: In this review, we mainly discuss the role of FXR in the pathophysiology of NAFLD and how it can be a useful treatment target for such patients.

Abbreviations

NAFLD: Non-Alcoholic Fatty Liver Disease; FXR: Farnesoid X Receptor; NASH: Non-Alcoholic Steatohepatitis; HCC: Hepatocellular Carcinoma; CYP7A1: Cholesterol-7α-hydroxylase; LDRL: LDL Receptor; SREBP-1c: Sterol Regulatory Element Binding Protein 1c; LDL: Low Density Lipoprotein; VLDL: Very Low Density Lipoprotein; FGF: Fibroblast Growth Factor; HDL: High Density Lipoprotein; Apo A-1: Apolipoprotein A-1; NASH: Non-Alcoholic Steatohepatitis; CDCA: Chenodeoxycholic; OCA: Obeticholic Acid

Background

The incidence and prevalence of non-alcoholic fatty liver disease (NAFLD) is on the rise with each passing decade and at present 25-35% and 5-15% of the general population of Western and Asian countries, respectively, are affected by this disease [1-3]. The spectrum of NAFLD ranges from benign steatosis to non-alcoholic steatohepatitis (NASH) to cirrhosis and finally to hepatocellular carcinoma (HCC). The exact pathophysiology of this disease is not completely understood but various risk factors such as obesity, type 2 diabetes mellitus and metabolic syndrome have been identified. The prevalence of NAFLD is much higher in patients with obesity (75-92%) and diabetes (60-70%) compared to the general population [4-7]. Most of the NAFLD patients have benign steatosis and are asymptomatic. However, 15-40% of such patients may progress to NASH which can be life threatening [8]. 15% of NASH patients can progress to cirrhosis in 10-15 years [9] and cirrhosis increases the risk of HCC by 10% [10,11]. In addition, NAFLD increases the risk for various other cancers, particularly in the gastrointestinal tract (colon, oesophagus, stomach, and pancreas) and extra-intestinal sites (kidney, prostate, breast) [12]. With the increase in incidence of NAFLD, the incidence of liver transplantation in such patients is also increasing. NASH is currently the second leading reason for liver transplantation and it is predicted that it will be the leading cause in the future [13,14]. With the increasing incidence of NAFLD, it has also been reported that hospitalisation and mortality in these patients is not mainly due to liver related causes but also due to cardiovascular and renal causes [15-19]. Thus NAFLD poses a serious health problem and up until now, no proper pathophysiological targeting treatment has been found. Treatment is mainly directed towards weight loss and risk factor reduction. A weight loss of 3-5% by diet modification and exercise has been shown to reduce steatosis while ≥5-7% drop in weight has shown to resolve NASH. Greater reductions in weight ≥10% may also improve hepatic fibrosis [20]. However, the shortcoming of this approach is the lack of adherence and non-compliance with time. [20-23]. Thus, an effective and safe therapeutic regimen is critically needed.

Farnesoid X receptor (FXR) is a nuclear hormone receptor, which is expressed in various organs and tissues, mainly in the liver, intestine, kidney, and adrenal cortex [24,25]. It is a ligand activated transcription factor, with bile acid being the natural ligand to these receptors [26]. These receptors are involved in regulating various metabolic pathways such as bile acid, cholesterol, and lipid and glucose metabolism [27,28]. The expression of FXR is reduced in the liver of NAFLD patients [29], and various FXR knockout animal models exhibit hepatic steatosis, bile acid accumulation, hyperlipidaemia, hyperglycaemia and fibrosis [30-32]. Importantly, these conditions are improved by increasing FXR expression [33,34], indicating that the FXR agonist could be an effective therapeutic option for NAFLD patients.

Isoforms of FXR

Until now, four FXR isoforms have been identified in humans. These four isoforms are derived from a single gene (NR1H4) in humans because of differential promoter usage and splicing at exon 5. These isoforms are classified as FXRα1 (+), FXRα1(-), FXRα2(+) and FXRα2(-). FXRα1 and FXRα2 differ in amino acid sequence at their amino terminus and both FXRα1(+) and FXRα2(+) contain a four amino acid (MYTG) insertion in the hinge region immediately adjacent to the DNA binding domain. This affects their ability to bind to FXR response elements (FXRE), thus making them less transcriptionally active [35,36]. All four isoforms occur in many tissues but FXRα1 is predominantly expressed in the liver and adrenals, whereas FXRα2 is mainly found in the intestine and kidney. In most cell types the strongest response was found to be that of FXRα1 (-). When the response of all four isoforms were studied, it was found that in liver cells, FXR induced BSEP (bile salt export pump) stimulating response was FXRα1(-) > FXRα2(-) > FXRα1(+) > FXRα2(+); for SHP (small heterodimer partner) it was FXRα1(-) = FXRα2(-) > FXRα1(+) = FXRα2(+). However, all of the isoforms showed the same efficiency for OST β (organic solute transporter β) expression. Also, the differential response for all the isoforms in intestinal cells for FGF19 (fibroblast growth factor 19) and IBABP (intestinal bile acid binding protein) expression was found to be somewhat similar to BSEP, with FXRα1 (+) and FXRα2(+) displaying same potency i.e., the order of magnitude for up regulation was FXRα1(-) > FXRα2(-) > FXRα1(+) = FXRv2(+) [37]. In a mouse model study addressing the role of FXRα1 (-) and FXRα2(-) on bile and lipid metabolism showed that these most active isoforms differentially regulate Cyp8b1and SHP expression. Both isoforms have been shown to reduce the elevated total plasma cholesterol levels, with FXRα1 (-) being more effective than FXRα2 (-), but neither completely normalized cholesterol levels to those seen in wild type mice [38-40]. FXRα2(-) was shown to differ from FXR1α (-) in their N-terminal parts with a 37 amino acid extension which must have contributed to conformational changes in the FXR protein and its transcriptional activity. Despite the identification of the four FXR isoforms, their detailed physiological roles, coregulator recruitment and DNA-binding in different tissues are still not clearly understood. Thus, for the purpose of this review, FXR will refer to all four isoforms.

Effects of FXR on multiple metabolic pathways

In addition to regulating various metabolic pathways as indicated above [27, 28], FXR also affects inflammation, fibrosis, liver regeneration and atherosclerosis [41,42].

Role of FXR in bile acid metabolism

The main role of FXR is to protect the hepatocytes by preventing accumulation of bile acid by inhibiting bile acid synthesis, reabsorption, and accelerating its excretion mainly at the hepatocytes and enterocytes level. Bile acid is a natural ligand for FXR and upon binding causes FXR activation which, in turn, leads to the suppression of cholesterol-7α-hydroxylase (CYP7A1), a key enzyme in bile acid synthesis. CYP7A1 is not directly suppressed by FXR, rather FXR increases the expression of the small heterodimer partner (SHP), which in turn inhibits the CYP7A1 gene [43,44]. FXR in enterocytes, upon activation by bile acid, induces fibroblast growth factor 19 (FGF 19) which upon binding to FGF4 receptors, causes inhibition of CYP7A1 via the JNK pathway [45-47]. FXR also regulates the enterohepatic circulation of bile acid. It does so by inhibiting the Na+-dependent taurocholate transporter which is responsible for bile acid transport, thus reducing uptake by the hepatocytes as well as up regulates the bile salt export pump, thus increasing bile acid export. FXR activation in enterocytes reduces the expression of apical sodium-dependent bile salt transporter which is mainly responsible for bile acid absorption at the terminal ileum, thus inhibiting its reabsorption. Moreover, the activation of FXR increases the expression of the cytosolic intestinal bile acid-binding protein (I-BABP), an important transport protein in the intestine which transports the BAs across the enterocytes and portal circulation to the liver [48,49]. Also it increases the expression of the organic solute transporter α/β (OST α/β), thus secreting bile acid into systemic circulation to be excreted via the kidney [50]. Thus, FXR activation in hepatocytes and enterocytes protect the hepatocytes from toxic accumulation of bile acids.

Role of FXR in cholesterol and lipid metabolism

Previous research has shown that bile can modulate cholesterol and lipid metabolism [51, 52]. The expression of FXR is reduced in the liver of NAFLD patients [29]. The relevance of FXR in modulating cholesterol homeostasis is evident from FXR knockout mice that exhibit increased hepatic and serum cholesterol levels [53,54]. FXR activation increases fecal cholesterol excretion by inhibiting intestinal cholesterol absorption [55,56]. Further, FXR activation decreases hepatic cholesterol uptake via increasing the expression of low density lipoprotein (LDL) receptor (LDLR), scavenger receptor class B type I and decreasing cluster differentiation protein 36 expression [54,57]. FXR activation also increases liver cholesterol excretion by increasing the expression of ATP-binding cassette G5/8 (ABCG5/G8), the cholesterol efflux transporter [58].

NAFLD patients exhibit high triglyceride levels due to the decreased FXR and increased SREBP-1c expression [29]. FXR activation significantly impacts lipid synthesis, mainly by decreasing the expression of the sterol regulatory element binding protein 1c (SREBP-1c) and its enzymes which are the main regulator in lipogenesis [59]. In addition, FXR activation increases the clearance of LDL, very low density lipoprotein (VLDL) and chylomicrons by activation of lipoprotein lipase [60], and increasing VLDL receptor expression [61]. Furthermore, FXR activation results in the induction of the peroxisome proliferator activated-α receptor which increases fatty acid oxidation [62]. Also it increases the secretion of FGF21 which decreases lipogenesis by inhibition of SREBP-1c [63,64].

Role of FXR in glucose homeostasis

FXR also plays a key role in a glucose homeostasis. FXR activation improves insulin sensitivity and decreases gluconeogenesis by suppression of phosphoenolpyruvate kinase and glucose-6-phosphatase which are the key enzymes required for gluconeogenesis [32, 65]. Further, by increasing FGF21 secretion, FXR induces the phosphorylation of glycogen synthase kinase which promotes glycogen synthesis and suppresses gluconeogenesis [66,67].

FXR is reported to exhibit anti- inflammatory and anti-fibrogenic properties. FXR activation decreases hepatic inflammation by suppressing the nuclear factor kappa B pathway [68]. Administration of the FXR agonist in a NAFLD animal model reduces various pro- inflammatory cytokines and growth factors [31]. FXR knockout mice have been shown to be more susceptible to lipopolysaccharide-induced liver injury, thus indicating that FXR has anti- inflammatory properties [68].

Anti-tumorigenic properties

FXR is a multi-functional receptor that also exhibits anti-tumorigenic properties. FXR knockout mice have been shown to develop liver tumours with aging [69,70], and FXR expression has been found to be significantly decreased in many human tumour specimens [71-74]. In FXR knockout mice excessive BA accumulation has been considered to have cytotoxic effects, thus favouring tumorigenesis [69,70,75]. Also, sharply increased BA levels lead to activation of YAP protein and Hippo pathway which is a crucial promoter of hepatocarcinogenesis [76-78]. NASH, obesity and diabetes mellitus have been considered to increase the risk of HCC; thus, by maintaining the homeostasis of glucose, lipid and by antagonizing the hepatic inflammation and fibrosis, FXR is believed to impede the progression of NASH to cirrhosis to HCC [60]. FXR also promotes liver regeneration by activating FoxM1b transcription factor [79]. FXR deficient mice display defective repair ability and delayed liver regeneration in an already damaged liver [79,80]. Moreover, it causes the inhibition of inflammatory signalling pathways like NFκB and STAT3 which play a key role in hepatic damage, fibrosis and act as a promoter of liver carcinogenesis [81-83]. Another FXR targeted gene is N-myc downstream regulated gene 2 (NDRG2- tumour suppressor gene). FXR knockout mice and human HCC patients have shown to have diminished levels of NDGR2 mRNA. FXR agonists or ectopic over-expression of FXR leads to the transcriptional induction of the NDRG2 gene [84]. Also, FXR has been shown to have a chemoprotective response on liver cells by changing the expression of several genes like ABCB4, TCEA2, CCL14, CCL15 and KRT13 which may be involved in drug efflux, DNA repair, and cell survival. This characteristic is shared by both healthy and tumour cells, thus playing an important role in the chemoprotection of healthy hepatocytes against genotoxic compounds and at same time reducing the response of liver tumor cells to certain pharmacological treatments [85].

Due to the FXR deficiency, hepatocytes are exposed to an environment which favours malignant transformation. Therefore, changing the FXR silencing or activation of remnant FXR may be potential strategies for liver cancer patients.

Pro-atherosclerotic properties

However, FXR activation has some concerning side effects. It increases the susceptibility to atherosclerosis by inhibiting the removal of cholesterol from peripheral cells via suppressing the expression of apolipoprotein A-1 (Apo A-1), a main constituent of high density lipoprotein (HDL) [86,87]. FXR activation also suppresses the paraoxonase 1 enzyme which plays a key role in inactivation of pro-atherogenic lipids [88,89]. Finally, FXR suppresses the action of proprotein convertase subtilisin/kexin 9 that promotes degradation of LDL [90,91]. Two phase I studies conducted in healthy individuals looking at the effects of FXR activation by OCA reported a decrease in HDL and increase in LDL cholesterol, regardless of the dose of OCA (5, 10 or 25 mg daily) after 14-20 days of treatment [92]. Similarly, treatment of NAFLD patients with OCA caused a 10% increase in total cholesterol, a 20% increase in LDL cholesterol and a 5% decrease in HDL cholesterol. Comparable reduction in HDL cholesterol was also reported in PBC patients treated with OCA. These effects are reversible after drug discontinuation [93-95]. These adverse side effects of FXR activation raise concern for its utility in treating NAFLD patients. The significance of these changes on cardiovascular outcomes needs to be explored more in any OCA based treatment strategy.

Role of FXR agonist in NAFLD treatment

At present there is no effective therapy for NAFLD and the treatment options are mainly directed towards lifestyle modification in the form of diet modification, weight loss and exercise as these factors improve obesity and insulin sensitivity. However, patient’s adherence to life style modification and compliance falls with time [96-98]. Liver transplantation is the only option left for NASH patients with cirrhosis. However, even after transplantation there is risk of recurrence of disease and cardiovascular complications [99].

As discussed, FXR play a key role in bile acid, cholesterol, lipid and glucose homeostasis; and also it is shown to have anti-inflammatory and anti-fibrogenic properties. These actions of FXR make it a suitable therapeutic option for NAFLD patients.

FXR agonist (GW4064) treatment in a preclinical study conducted in a genetically obese mouse with insulin resistance improved insulin sensitivity and glucose clearance when compared to controls [100]. Further, treatment of FXR+/+ and FXR-/- mice with GW4064 showed a significant decrease of plasma glucose and fatty acids in FXR+/+ mice [67]. Similar efficacy of the FXR agonist was observed in a diabetic mouse model [67]. GW4064 increases the expression of p62/SQSTM1 and nuclear factor erythroid 2-related factor-2 (Nrf2) resulting in the induction of various antioxidant and anti-apoptotic molecules [101]. Furthermore, administration of an FXR agonist (WAY 362450) to a methionine and choline deficient, diet-induced animal model of NASH, exhibited a significant reduction in liver transaminases enzymes. Also, a significant decrease in hepatic fibrosis and inflammatory cell infiltration and cytokines were observed [34]. Recently, a novel, non-steroidal FXR agonist, PX20606, has been shown to have anti-fibrotic and vasodilator properties and lowers portal hypertension [102]. A newly found non-bile steroidal dual ligand for FXR and GPBAR1 receptors, BAR502, reverses high-fat diet induced steatohepatitis in mice by promoting the browning of adipose tissue [103]. All of these results indicate that the FXR agonist could be an effective treatment option for NAFLD patients.

Of all the synthetically derived FXR agonists, the most clinically advanced is INT-747/Obeticholic acid (OCA) which is a semi-synthetic derivative of a natural bile acid analogue, chenodeoxycholic acid (CDCA), with an affinity 100 times greater than CDCA [104, 105]. Preclinical studies of OCA in the Zucker (fa/fa) rat, a NAFLD rat model, resulted in reduction of gluconeogenesis, lipogenesis and improvement of insulin resistance and hepatic steatosis [33]. In a rat model of thioacetamide-induced cirrhosis, OCA reduced hepatic inflammation and fibrosis and also decreased intrahepatic vascular resistance and improved portal hypertension [106]. In a rabbit model of high fat diet-induced NAFLD, administration of OCA resulted in an improvement in visceral fat and plasma glucose levels [107]. In addition, OCA administration reduces liver transaminases, IFN- gamma and TNF-α in an autoimmune hepatitis mouse model [108]. FXR activation has been shown to promote hepatic amino acid catabolism and ammonium clearance via ureagenesis and glutamine synthesis [109]. OCA also decreases intestinal inflammation in various colitis animal models [110]. In an animal model with advanced cirrhosis, treatment with OCA significantly reduced gut bacterial translocation [111]. Additional miR-21 ablation with FXR activation by OCA ameliorated NASH suggesting that a multi-receptor targeting therapy could be the most effective treatment strategy [112].

OCA is the only FXR agonist which has been examined in clinical trials on NAFLD patients. Its role has been investigated in two large randomized controlled trials (NCT00501592 and NCT01265498). The first trial was conducted on NAFLD and type 2 diabetes mellitus patients (NCT00501592), in which patients were randomly distributed in any of the three groups receiving placebo or 25 mg or 50 mg OCA for a period of 6 weeks. It was noticed that patients receiving 25 mg and 50 mg of OCA showed improvement in insulin sensitivity by 28% and 21%, respectively, while it worsened in the placebo arm by 5%. Weight loss was noticed in both the OCA groups but hepatic fibrosis improved only in patients on the 25 mg OCA regimen. An increase in alkaline phosphatase, with a decrease in alanine transaminase and γ-glutamyltransferase levels was noticed in both OCA-treated groups. While aspartate transaminase levels remained stable in all, a decrease in HDL and an increase in LDL were noticed in patients treated with 50 mg OCA [113].

Recently, OCA treatment was used in another large trial, the FLINT trial (NCT01265498), which included NASH patients with or without cirrhosis. In this multicentre trial, 283 patients were randomly distributed in either placebo or 25 mg OCA arm for 72 weeks. Here 45% of the patients in the OCA arm and 21% of the patients in the placebo arm met the primary outcome of the study which was determined to be a drop of 2 points in the NAFLD activity score. In addition to this, 35% of the patients in the OCA arm and 19% in the placebo arm showed a reduction in hepatic fibrosis. OCA group patients showed a reduction in body weight, liver transaminases and systolic blood pressure but an increase in plasma glucose levels and insulin resistance. Pruritus was noticed as the main side effect in the patients in the OCA group [114]. A Phase 3, Double-blind RCT Multicenter Study is ongoing to evaluate the safety and efficacy of OCA in NASH patients (ClinicalTrials.gov Identifier: NCT02548351). This trial evaluates the effect of OCA compared to placebo on liver histology in non-cirrhotic NASH patients with stage 2 or 3 fibrosis. 2065 patients are randomized in 1:1:1 to placebo, 10 mg or 25 mg OCA. An interim analysis is to be done at 18 months and the study is expected to end in 6 years (https://clinicaltrials.gov/ct2/show/NCT02548351).

All of the preclinical animal/human and clinical human studies suggest that FXR agonist/OCA can be a potential therapeutic option in NAFLD patients. However, OCA produces pro-atherogenic effects that can be a concern for NAFLD patients with a high risk for cardiovascular adverse events. Therefore, long term larger clinical trials are required to determine its efficacy and safety. Further, combination therapies with FXR agonist and agents that prevent atherosclerosis are warranted.

Conclusions

The FXR agonist appears to be an attractive drug due to its pleiotropic actions of regulating various metabolic pathways. They play a critical role in bile acid, lipid, cholesterol, and glucose homeostasis. In addition, they also have anti-inflammatory and anti-fibrogenic properties. The data presented from various preclinical and clinical studies suggest that it can be a good therapeutic option in the prevention and treatment of NAFLD. However, several undesirable results such as a decrease in plasma HDL is concerning. Therefore, larger, long-term clinical trials are required to determine its efficacy and safety. Further, combination therapies with FXR agonist and agents that prevent atherosclerosis are warranted. Furthermore, we should continue to gain a better understanding of NAFLD pathogenesis such that additional molecular targets and cellular pathways could be identified for developing other novel therapeutic regimen(s) in the future.

We acknowledge the use of the facilities at the Omaha Veterans Affairs’ Medical Center and a Merit Review BX001155 grant support (KKK) from the Department of Veterans Affairs, Office of Research and Development (Biomedical Laboratory Research and Development).

1. Masarone M, Federico A, Abenavoli L, Loguercio C, Persico M (2014) Non alcoholic fatty liver: epidemiology and natural history. Rev Recent Clin Trials 9: 126-133. Link: https://goo.gl/CdmajH
2. Chitturi S, Wong VW, Farrell G (2011) Nonalcoholic fatty liver in Asia: Firmly entrenched and rapidly gaining ground. J Gastroenterol Hepatol 26: 163-172. Link: https://goo.gl/KVXdGP
3. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L (2016) Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 64:73-84. Link: https://goo.gl/8QzfCx
4. Giday SA, Ashiny Z, Naab T, Smoot D, Banks A (2006) Frequency of nonalcoholic fatty liver disease and degree of hepatic steatosis in African-American patients. J Natl Med Assoc 98: 1613-1615. Link: https://goo.gl/W8SQB8
5. Jimba S, Nakagami T, Takahashi M, Wakamatsu T, Hirota Y, et al. (2005) Prevalence of non-alcoholic fatty liver disease and its association with impaired glucose metabolism in Japanese adults. Diabet Med 22:1141-1145. Link: https://goo.gl/Tttiyi
6. Ballestri S, Zona S, Targher G, Romagnoli D, Baldelli E, et al. (2016) Nonalcoholic fatty liver disease is associated with an almost twofold increased risk of incident type 2 diabetes and metabolic syndrome. Evidence from a systematic review and meta-analysis. J Gastroenterol Hepatol 31: 936-944. Link: https://goo.gl/C3KfoW
7. Lonardo A, Ballestri S, Guaraldi G, Nascimbeni F, Romagnoli D, et al. (2016) Fatty liver is associated with an increased risk of diabetes and cardiovascular disease - Evidence from three different disease models: NAFLD, HCV and HIV. World J Gastroenterol 22: 9674-9693. Link: https://goo.gl/9FAPlp
8. De Alwis NM, Day CP (2008) Non-alcoholic fatty liver disease: the mist gradually clears. J Hepatol. 48 Suppl 1: 104-112. Link: https://goo.gl/ldpflB
9. Targher G, Arcaro G (2007) Non-alcoholic fatty liver disease and increased risk of cardiovascular disease. Atherosclerosis 191: 235-240. Link: https://goo.gl/yufyf8
10. Ekstedt M, Franzen LE, Mathiesen UL, Thorelius L, Holmqvist M, et al. (2006) Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 44: 865-873. Link: https://goo.gl/QbXmTP
11. Piscaglia F, Svegliati-Baroni G, Barchetti A, Pecorelli A, Marinelli S, et al. (2016) Clinical patterns of hepatocellular carcinoma in nonalcoholic fatty liver disease: A multicenter prospective study. Hepatology 63: 827-838. Link: https://goo.gl/b9unqu
12. Sanna C, Rosso C, Marietti M, Bugianesi E (2016) Non-Alcoholic Fatty Liver Disease and Extra-Hepatic Cancers. Int J Mol Sci 17. Link: https://goo.gl/nREW3S  
13. Wong RJ, Cheung R, Ahmed A (2014) Nonalcoholic steatohepatitis is the most rapidly growing indication for liver transplantation in patients with hepatocellular carcinoma in the U.S. Hepatology 59: 2188-2195. Link: https://goo.gl/j1aFvc
14. Pais R, Barritt ASt, Calmus Y, Scatton O, Runge T, Lebray P, et al. (2016) NAFLD and liver transplantation: Current burden and expected challenges. J Hepatol 65: 1245-1257. Link: https://goo.gl/oS0hjp
15. El Azeem HA, Khalek el SA, El-Akabawy H, Naeim H, Khalik HA, et al. (2013) Association between nonalcoholic fatty liver disease and the incidence of cardiovascular and renal events. J Saudi Heart Assoc 25: 239-246. Link: https://goo.gl/ugw5pG
16. Targher G, Chonchol M, Zoppini G, Abaterusso C, Bonora E (2011) Risk of chronic kidney disease in patients with non-alcoholic fatty liver disease: is there a link? J Hepatol 54:1020-1029. Link: https://goo.gl/cbS6HW
17. Federico A, Dallio M, Masarone M, Persico M, Loguercio C. (2016) The epidemiology of non-alcoholic fatty liver disease and its connection with cardiovascular disease: role of endothelial dysfunction. Eur Rev Med Pharmacol Sci 20: 4731-4741. Link:  https://goo.gl/i4hEUI
18. Lonardo A, Sookoian S, Pirola CJ, Targher G (2016) Non-alcoholic fatty liver disease and risk of cardiovascular disease. Metabolism 65: 1136-1150. Link: https://goo.gl/ytlZyq
19. Valbusa F, Bonapace S, Grillo C, Scala L, Chiampan A, et al. (2016) Nonalcoholic Fatty Liver Disease Is Associated With Higher 1-year All-Cause Rehospitalization Rates in Patients Admitted for Acute Heart Failure. Medicine (Baltimore) 95: 2760. Link: https://goo.gl/KjlJdm
20. Hannah WN, Jr., Harrison SA (2016) Lifestyle and Dietary Interventions in the Management of Nonalcoholic Fatty Liver Disease. Dig Dis Sci 61: 1365-1374. Link: https://goo.gl/2nNCll
21. Bellentani S, Dalle Grave R, Suppini A, Marchesini G, Fatty Liver Italian N. (2008) Behavior therapy for nonalcoholic fatty liver disease: The need for a multidisciplinary approach. Hepatology 47: 746-754. Link: https://goo.gl/SBWSHf
22. Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, et al. (2012) The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology 55: 2005-2023. Link: https://goo.gl/Syrq44
23. Musso G, Gambino R, Cassader M, Pagano G (2010) A meta-analysis of randomized trials for the treatment of nonalcoholic fatty liver disease. Hepatology 52: 79-104. Link: https://goo.gl/8vYo4u
24. Lefebvre P, Cariou B, Lien F, Kuipers F, Staels B. (2009) Role of bile acids and bile acid receptors in metabolic regulation. Physiol Rev 89: 147-191. Link: https://goo.gl/rYM5Zk
25. Thomas C, Pellicciari R, Pruzanski M, Auwerx J, Schoonjans K (2008) Targeting bile-acid signalling for metabolic diseases. Nat Rev Drug Discov 7: 678-693. Link: https://goo.gl/8YtEs5
26. Parks DJ, Blanchard SG, Bledsoe RK, Chandra G, Consler TG, et al. (1999) Bile acids: natural ligands for an orphan nuclear receptor. Science 284: 1365-1368. Link: https://goo.gl/4JbNVK
27. Wang YD, Chen WD, Moore DD, Huang W (2008) FXR: a metabolic regulator and cell protector. Cell Res 18:1087-1095. Link: https://goo.gl/4HkoUs
28. Laffitte BA, Kast HR, Nguyen CM, Zavacki AM, Moore DD, et al. (2000) Identification of the DNA binding specificity and potential target genes for the farnesoid X-activated receptor. J Biol Chem 275: 10638-10647. Link: https://goo.gl/VnbYZe
29. Yang ZX, Shen W, Sun H (2010) Effects of nuclear receptor FXR on the regulation of liver lipid metabolism in patients with non-alcoholic fatty liver disease. Hepatol Int 4: 741-748. Link: https://goo.gl/TthqrY
30. Bjursell M, Wedin M, Admyre T, Hermansson M, Bottcher G, et al. (2013) Ageing Fxr deficient mice develop increased energy expenditure, improved glucose control and liver damage resembling NASH. PLoS One 8:e64721. Link: https://goo.gl/Qb9a21
31. Kong B, Luyendyk JP, Tawfik O, Guo GL (2009) Farnesoid X receptor deficiency induces nonalcoholic steatohepatitis in low-density lipoprotein receptor-knockout mice fed a high-fat diet. J Pharmacol Exp Ther 328: 116-122. Link: https://goo.gl/WOQAC8
32. Ma K, Saha PK, Chan L, Moore DD (2006) Farnesoid X receptor is essential for normal glucose homeostasis. J Clin Invest 116: 1102-1109. Link: https://goo.gl/NX2obD
33. Cipriani S, Mencarelli A, Palladino G, Fiorucci S. (2010) FXR activation reverses insulin resistance and lipid abnormalities and protects against liver steatosis in Zucker (fa/fa) obese rats. J Lipid Res 51: 771-784. Link: https://goo.gl/WV0vmR
34. Zhang S, Wang J, Liu Q, Harnish DC. (2009) Farnesoid X receptor agonist WAY-362450 attenuates liver inflammation and fibrosis in murine model of non-alcoholic steatohepatitis. J Hepatol 51: 380-388. Link: https://goo.gl/bREE6K
35. Huber RM, Murphy K, Miao B, Link JR, Cunningham MR, et al. (2002) Generation of multiple farnesoid-X-receptor isoforms through the use of alternative promoters. Gene 290: 35-43. Link: https://goo.gl/LeF1UX
36. Lee FY, Lee H, Hubbert ML, Edwards PA, Zhang Y (2006) FXR, a multipurpose nuclear receptor. Trends Biochem Sci 31: 572-580. Link: https://goo.gl/IuwIUo
37. Vaquero J, Monte MJ, Dominguez M, Muntane J, Marin JJ (2013) Differential activation of the human farnesoid X receptor depends on the pattern of expressed isoforms and the bile acid pool composition. Biochem Pharmacol 86: 926-939. Link: https://goo.gl/LEskT5
38. Kok T, Hulzebos CV, Wolters H, Havinga R, Agellon LB, et al. (2003) Enterohepatic circulation of bile salts in farnesoid X receptor-deficient mice: efficient intestinal bile salt absorption in the absence of ileal bile acid-binding protein. J Biol Chem 278: 41930-41937. Link: https://goo.gl/aKZZSb  
39. Zhang Y, Kast-Woelbern HR, Edwards PA (2003) Natural structural variants of the nuclear receptor farnesoid X receptor affect transcriptional activation. J Biol Chem 278: 104-110. Link: https://goo.gl/8GEQWt
40. Boesjes M, Bloks VW, Hageman J, Bos T, van Dijk TH, et al. (2014) Hepatic farnesoid X-receptor isoforms alpha2 and alpha4 differentially modulate bile salt and lipoprotein metabolism in mice. PLoS One 9:e115028. Link: https://goo.gl/d50aIC
41. Fiorucci S, Rizzo G, Antonelli E, Renga B, Mencarelli A, et al. (2005) A farnesoid x receptor-small heterodimer partner regulatory cascade modulates tissue metalloproteinase inhibitor-1 and matrix metalloprotease expression in hepatic stellate cells and promotes resolution of liver fibrosis. J Pharmacol Exp Ther 314: 584-595. Link: https://goo.gl/0Dz3BP
42. Mencarelli A, Renga B, Distrutti E, Fiorucci S (2009) Antiatherosclerotic effect of farnesoid X receptor. Am J Physiol Heart Circ Physiol 296: 272-281. Link: https://goo.gl/0mZ8zN
43. Rizzo G, Renga B, Mencarelli A, Pellicciari R, Fiorucci S (2005) Role of FXR in regulating bile acid homeostasis and relevance for human diseases. Curr Drug Targets Immune Endocr Metabol Disord 5: 289-303. Link: https://goo.gl/b4NxJd
44. Ballestri S, Nascimbeni F, Romagnoli D, Baldelli E, Lonardo A. (2016) The Role of Nuclear Receptors in the Pathophysiology, Natural Course, and Drug Treatment of NAFLD in Humans. Adv Ther 33: 291-319. Link: https://goo.gl/l3jWVX
45. Chen Q, Jiang Y, An Y, Zhao N, Zhao Y, et al. (2011) Soluble FGFR4 extracellular domain inhibits FGF19-induced activation of FGFR4 signaling and prevents nonalcoholic fatty liver disease. Biochem Biophys Res Commun 409: 651-656. Link: https://goo.gl/1l0DK8
46. Inagaki T, Choi M, Moschetta A, Peng L, Cummins CL, et al. (2005) Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab 2: 217-225. Link: https://goo.gl/SWgx25
47. Song KH, Li T, Owsley E, Strom S, Chiang JY (2009) Bile acids activate fibroblast growth factor 19 signaling in human hepatocytes to inhibit cholesterol 7alpha-hydroxylase gene expression. Hepatology 49: 297-305. Link: https://goo.gl/0Hywf5
48. Li T, Chiang JY. (2012) Bile Acid signaling in liver metabolism and diseases. J Lipids 2012: 754067. Link: https://goo.gl/z0G1vh
49. Geier A, Wagner M, Dietrich CG, Trauner M. (2007) Principles of hepatic organic anion transporter regulation during cholestasis, inflammation and liver regeneration. Biochim Biophys Acta 1773: 283-308. Link: https://goo.gl/Wk8MFw
50. Boyer JL, Trauner M, Mennone A, Soroka CJ, Cai SY, et al. (2006) Upregulation of a basolateral FXR-dependent bile acid efflux transporter OSTalpha-OSTbeta in cholestasis in humans and rodents. Am J Physiol Gastrointest Liver Physiol 290: 1124-1130. Link: https://goo.gl/HUxb6I  
51. Nestel PJ, Grundy SM (1976) Changes in plasma triglyceride metabolism during withdrawal of bile. Metabolism 25: 1259-1268. Link: https://goo.gl/HBVBBS
52. Grundy SM, Ahrens EH, Jr., Salen G (1971) Interruption of the enterohepatic circulation of bile acids in man: comparative effects of cholestyramine and ileal exclusion on cholesterol metabolism. J Lab Clin Med 78: 94-121. Link: https://goo.gl/3GgphZ
53. Sinal CJ, Tohkin M, Miyata M, Ward JM, Lambert G, et al. (2000) Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell 102: 731-744. Link: https://goo.gl/yi2Mgq
54. Lambert G, Amar MJ, Guo G, Brewer HB,Gonzalez FJ, et al. (2003) The farnesoid X-receptor is an essential regulator of cholesterol homeostasis. J Biol Chem 278: 2563-2570. Link: https://goo.gl/LLSeOp
55. de Boer JF, Schonewille M, Boesjes M, Wolters H, Bloks VW, et al. (2017) Intestinal Farnesoid X Receptor Controls Transintestinal Cholesterol Excretion in Mice. Gastroenterology 152: 1126-1138. Link: https://goo.gl/qcc3SK
56. Xu Y, Li F, Zalzala M, Xu J, Gonzalez FJ, et al. (2016) Farnesoid X receptor activation increases reverse cholesterol transport by modulating bile acid composition and cholesterol absorption in mice. Hepatology 64: 1072-1085. Link: https://goo.gl/jOoq7l
57. Van Rooyen DM, Larter CZ, Haigh WG, Yeh MM, Ioannou G, et al. (2011) Hepatic free cholesterol accumulates in obese, diabetic mice and causes nonalcoholic steatohepatitis. Gastroenterology 141: 1393-1403. Link: https://goo.gl/Cuhhwa
58. Li T, Matozel M, Boehme S, Kong B, Nilsson LM, et al. (2011) Overexpression of cholesterol 7alpha-hydroxylase promotes hepatic bile acid synthesis and secretion and maintains cholesterol homeostasis. Hepatology 53: 996-1006. Link: https://goo.gl/QGbAmB
59. Horton JD, Goldstein JL, Brown MS. (2002) SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest 109: 1125-1131. Link: https://goo.gl/gdZEcP
60. Fuchs M (2012) Non-alcoholic Fatty liver disease: the bile Acid-activated farnesoid x receptor as an emerging treatment target. J Lipids 2012: 934396. Link: https://goo.gl/Eva8vB
61. Sirvent A, Claudel T, Martin G, Brozek J, Kosykh V, et al. (2004) The farnesoid X receptor induces very low density lipoprotein receptor gene expression. FEBS Lett 566: 173-177. Link: https://goo.gl/UhfEcu
62. Pineda Torra I, Claudel T, Duval C, Kosykh V, Fruchart JC, et al. (2003) Bile acids induce the expression of the human peroxisome proliferator-activated receptor alpha gene via activation of the farnesoid X receptor. Mol Endocrinol 17: 259-272. Link: https://goo.gl/pDZsWB
63. Cyphert HA, Ge X, Kohan AB, Salati LM, Zhang Y, et al. (2012) Activation of the farnesoid X receptor induces hepatic expression and secretion of fibroblast growth factor 21. J Biol Chem 287: 25123-25138. Link: https://goo.gl/qaaVwz
64. Xu J, Lloyd DJ, Hale C, Stanislaus S, Chen M, et al. (2009) Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice. Diabetes 58: 250-259. Link: https://goo.gl/xTok2y
65. Kim SG, Kim BK, Kim K, Fang S (2016) Bile Acid Nuclear Receptor Farnesoid X Receptor: Therapeutic Target for Nonalcoholic Fatty Liver Disease. Endocrinol Metab 31: 500-504. Link: https://goo.gl/exQW3V
66. Seo JA, Kim NH (2012) Fibroblast growth factor 21: a novel metabolic regulator. Diabetes Metab J 36: 26-28. Link: https://goo.gl/fBDlHk
67. Zhang Y, Lee FY, Barrera G, Lee H, Vales C, Gonzalez FJ, et al. (2006) Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice. Proc Natl Acad Sci U S A 103: 1006-1011. Link: https://goo.gl/sNWHqQ
68. Wang YD, Chen WD, Wang M, Yu D, Forman BM, Huang W (2008) Farnesoid X receptor antagonizes nuclear factor kappaB in hepatic inflammatory response. Hepatology 48: 1632-1643. Link: https://goo.gl/BL2RhT
69. Kim I, Morimura K, Shah Y, Yang Q, Ward JM, et al. (2007) Spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice. Carcinogenesis 28: 940-946. Link: https://goo.gl/Boh60t
70. Yang F, Huang X, Yi T, Yen Y, Moore DD, et al. (2007) Spontaneous development of liver tumors in the absence of the bile acid receptor farnesoid X receptor. Cancer Res 67: 863-867. Link: https://goo.gl/B2dqMo
71. Jiang Y, Iakova P, Jin J, Sullivan E, Sharin V, et al. (2013) Farnesoid X receptor inhibits gankyrin in mouse livers and prevents development of liver cancer. Hepatology 57: 1098-1106. Link: https://goo.gl/XJUvDc
72. Liu N, Meng Z, Lou G, Zhou W, Wang X, et al. (2012) Hepatocarcinogenesis in FXR-/- mice mimics human HCC progression that operates through HNF1alpha regulation of FXR expression. Mol Endocrinol 26: 775-785. Link: https://goo.gl/JqQ8Rs
73. Su H, Ma C, Liu J, Li N, Gao M, et al. (2012) Downregulation of nuclear receptor FXR is associated with multiple malignant clinicopathological characteristics in human hepatocellular carcinoma. Am J Physiol Gastrointest Liver Physiol 303: 1245-1253. Link: https://goo.gl/WTnFeG
74. Torres J, Bao X, Iuga AC, Chen A, Harpaz N, et al. (2013) Farnesoid X receptor expression is decreased in colonic mucosa of patients with primary sclerosing cholangitis and colitis-associated neoplasia. Inflamm Bowel Dis 19: 275-282. Link: https://goo.gl/MNsJ5q  
75. Bernstein C, Holubec H, Bhattacharyya AK, Nguyen H, Payne CM, et al. (2011) Carcinogenicity of deoxycholate, a secondary bile acid. Arch Toxicol 85: 863-871. Link: https://goo.gl/U2gDnP
76. Anakk S, Bhosale M, Schmidt VA, Johnson RL, Finegold MJ, et al. (2013) Bile acids activate YAP to promote liver carcinogenesis. Cell Rep 5: 1060-1069. Link: https://goo.gl/hZnVUU
77. Lu L, Li Y, Kim SM, Bossuyt W, Liu P, Qiu Q, et al. (2010) Hippo signaling is a potent in vivo growth and tumor suppressor pathway in the mammalian liver. Proc Natl Acad Sci USA 107: 1437-1442. Link: https://goo.gl/J13Azq
78. Zhou D, Conrad C, Xia F, Park JS, Payer B, et al. (2009) Mst1 and Mst2 maintain hepatocyte quiescence and suppress hepatocellular carcinoma development through inactivation of the Yap1 oncogene. Cancer Cell. 16:425-438. Link: https://goo.gl/SQJBC6
79. Huang W, Ma K, Zhang J, Qatanani M, Cuvillier J, et al. (2006) Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration. Science 312: 233-236. Link: https://goo.gl/x7jMQs   
80. Borude P, Edwards G, Walesky C, Li F, Ma X, et al. (2012) Hepatocyte-specific deletion of farnesoid X receptor delays but does not inhibit liver regeneration after partial hepatectomy in mice. Hepatology 56: 2344-2352. Link: https://goo.gl/gZlUor
81. Grivennikov SI, Karin M. (2010) Dangerous liaisons: STAT3 and NF-kappaB collaboration and crosstalk in cancer. Cytokine Growth Factor Rev 21: 11-19. Link: https://goo.gl/jN4xHR
82. He G, Yu GY, Temkin V, Ogata H, Kuntzen C, et al. (2010) Hepatocyte IKKbeta/NF-kappaB inhibits tumor promotion and progression by preventing oxidative stress-driven STAT3 activation. Cancer Cell 17: 286-297. Link: https://goo.gl/8PZEQw
83. Li G, Zhu Y, Tawfik O, Kong B, Williams JA, et al. (2013) Mechanisms of STAT3 activation in the liver of FXR knockout mice. Am J Physiol Gastrointest Liver Physiol 305: 829-837. Link: https://goo.gl/NgMhAr
84. Deuschle U, Schuler J, Schulz A, Schluter T, Kinzel O, et al. (2012) FXR controls the tumor suppressor NDRG2 and FXR agonists reduce liver tumor growth and metastasis in an orthotopic mouse xenograft model. PLoS One 7:e43044. Link: https://goo.gl/ciThoz
85. Vaquero J, Briz O, Herraez E, Muntane J, Marin JJ (2013) Activation of the nuclear receptor FXR enhances hepatocyte chemoprotection and liver tumor chemoresistance against genotoxic compounds. Biochim Biophys Acta 1833: 2212-2219. Link: https://goo.gl/aADTxW
86. Fuchs M, Ivandic B, Muller O, Schalla C, Scheibner J, et al. (2001) Biliary cholesterol hypersecretion in gallstone-susceptible mice is associated with hepatic up-regulation of the high-density lipoprotein receptor SRBI. Hepatology 33: 1451-1459. Link: https://goo.gl/NaNumq
87. Claudel T, Sturm E, Duez H, Torra IP, Sirvent A, et al. (2002) Bile acid-activated nuclear receptor FXR suppresses apolipoprotein A-I transcription via a negative FXR response element. J Clin Invest 109: 961-971. Link: https://goo.gl/Iw4sKt
88. Gutierrez A, Ratliff EP, Andres AM, Huang X, McKeehan WL, et al. (2006) Bile acids decrease hepatic paraoxonase 1 expression and plasma high-density lipoprotein levels via FXR-mediated signaling of FGFR4. Arterioscler Thromb Vasc Biol 26: 301-306. Link: https://goo.gl/sNmoIA
89. Shih DM, Kast-Woelbern HR, Wong J, Xia YR, Edwards PA, et al. (2006) A role for FXR and human FGF-19 in the repression of paraoxonase-1 gene expression by bile acids. J Lipid Res 47: 384-392. Link: https://goo.gl/P18S0X
90. Langhi C, Le May C, Kourimate S, Caron S, Staels B, et al. (2008) Activation of the farnesoid X receptor represses PCSK9 expression in human hepatocytes. FEBS Lett 582: 949-955. Link: https://goo.gl/kwFZEb
91. Ghosh Laskar M, Eriksson M, Rudling M, Angelin B (2017) Treatment with the natural FXR agonist chenodeoxycholic acid reduces clearance of plasma LDL whilst decreasing circulating PCSK9, lipoprotein(a) and apolipoprotein C-III. J Intern Med 281: 575–585. Link: https://goo.gl/QmdXXe 
92. Pencek R, Marmon T, Roth JD, Liberman A, Hooshmand-Rad R, et al. (2016) Effects of obeticholic acid on lipoprotein metabolism in healthy volunteers. Diabetes Obes Metab 18: 936-940. Link: https://goo.gl/V5Ihvh
93. Hirschfield GM, Mason A, Luketic V, Lindor K, Gordon SC, et al. (2015) Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. Gastroenterology 148: 751-776. Link: https://goo.gl/NoYI6S
94. Makri E, Cholongitas E, Tziomalos K (2016) Emerging role of obeticholic acid in the management of nonalcoholic fatty liver disease. World J Gastroenterol 22:9039-9043. Link: https://goo.gl/ZvGJkD
95. Arab JP, Karpen SJ, Dawson PA, Arrese M, Trauner M (2017) Bile acids and nonalcoholic fatty liver disease: Molecular insights and therapeutic perspectives. Hepatology 65: 350-362. Link: https://goo.gl/SgzUDH
96. Tilg H, Moschen A (2010) Weight loss: cornerstone in the treatment of non-alcoholic fatty liver disease. Minerva Gastroenterol Dietol 56: 159-167. Link: https://goo.gl/6XtTn4
97. Akyuz F, Demir K, Ozdil S, Aksoy N, Poturoglu S, et al. (2007) The effects of rosiglitazone, metformin, and diet with exercise in nonalcoholic fatty liver disease. Dig Dis Sci 52: 2359-2367. Link: https://goo.gl/hMwNPi
98. Harrison SA, Day CP (2007) Benefits of lifestyle modification in NAFLD. Gut 56: 1760-1769. Link: https://goo.gl/CNXMLE
99. Vanwagner LB, Bhave M, Te HS, Feinglass J, Alvarez L, et al. (2012) Patients transplanted for nonalcoholic steatohepatitis are at increased risk for postoperative cardiovascular events. Hepatology 56: 1741-1750. Link: https://goo.gl/Pgqevo
100. Cariou B, van Harmelen K, Duran-Sandoval D, van Dijk TH, Grefhorst A, et al. (2006) The farnesoid X receptor modulates adiposity and peripheral insulin sensitivity in mice. J Biol Chem 281: 11039-11049. Link: https://goo.gl/dUhRHk
101. Haga S, Yimin, Ozaki M. (2017) Relevance of FXR-p62/SQSTM1 pathway for survival and protection of mouse hepatocytes and liver, especially with steatosis. BMC Gastroenterol 17: 19. Link: https://goo.gl/XIzdmq
102. Schwabl P, Hambruch E, Seeland BA, Hayden H, Wagner M, et al. (2017) The FXR agonist PX20606 ameliorates portal hypertension by targeting vascular remodelling and sinusoidal dysfunction. J Hepatol 66: 724-733. Link: https://goo.gl/oMVk1H
103. Carino A, Cipriani S, Marchiano S, Biagioli M, Santorelli C, et al. (2017) BAR502, a dual FXR and GPBAR1 agonist, promotes browning of white adipose tissue and reverses liver steatosis and fibrosis. Sci Rep 7: 42801. Link: https://goo.gl/196Bf2
104. Wang H, Chen J, Hollister K, Sowers LC, Forman BM (1999) Endogenous bile acids are ligands for the nuclear receptor FXR/BAR. Mol Cell 3: 543-553. Link: https://goo.gl/Of8LfV
105. Adorini L, Pruzanski M, Shapiro D (2012) Farnesoid X receptor targeting to treat nonalcoholic steatohepatitis. Drug Discov Today 17: 988-997. Link: https://goo.gl/pAqKpC
106. Verbeke L, Mannaerts I, Schierwagen R, Govaere O, Klein S, et al. (2016) FXR agonist obeticholic acid reduces hepatic inflammation and fibrosis in a rat model of toxic cirrhosis. Sci Rep. 6:33453. Link: https://goo.gl/zhpTCz
107. Vignozzi L, Morelli A, Filippi S, Comeglio P, Chavalmane AK, et al. (2011) Farnesoid X receptor activation improves erectile function in animal models of metabolic syndrome and diabetes. J Sex Med 8: 57-77. Link: https://goo.gl/eaoCTh
108. Mencarelli A, Renga B, Migliorati M, Cipriani S, Distrutti E, et al. (2009) The bile acid sensor farnesoid X receptor is a modulator of liver immunity in a rodent model of acute hepatitis. J Immunol 183: 6657-6666. Link: https://goo.gl/922Y1R
109. Massafra V, Milona A, Vos HR, Ramos RJJ, Gerrits J, et al. (2017) Farnesoid X Receptor Activation Promotes Hepatic Amino Acid Catabolism and Ammonium Clearance in Mice. Gastroenterology 152: 1462-1476. Link: https://goo.gl/3yrASX
110. Gadaleta RM, van Erpecum KJ, Oldenburg B, Willemsen EC, Renooij W, et al. (2011) Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease. Gut 60: 463-472. Link: https://goo.gl/vcFoI7
111. Ubeda M, Lario M, Munoz L, Borrero MJ, Rodriguez-Serrano M, et al. (2016) Obeticholic acid reduces bacterial translocation and inhibits intestinal inflammation in cirrhotic rats. J Hepatol 64: 1049-1057. Link: https://goo.gl/ukwrsA
112. Rodrigues PM, Afonso MB, Simao AL, Carvalho CC, Trindade A, et al. (2017) miR-21 ablation and obeticholic acid ameliorate nonalcoholic steatohepatitis in mice. Cell Death Dis. 8:e2748. Link: https://goo.gl/QncXL9
113. Mudaliar S, Henry RR, Sanyal AJ, Morrow L, Marschall HU, et al. (2013) Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology 145: 574-582 e1. Link: https://goo.gl/9VHQ77
114. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, Van Natta ML, et al. (2015) Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 385: 956-965. Link: https://goo.gl/oniN4J