Elsevier

Molecular Aspects of Medicine

Volume 56, August 2017, Pages 34-44
Molecular Aspects of Medicine

The role of bile acids in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis

https://doi.org/10.1016/j.mam.2017.04.004Get rights and content

Abstract

Nonalcoholic fatty liver disease is growing in prevalence worldwide. It is marked by the presence of macrosteatosis on liver histology but is often clinically asymptomatic. However, it can progress into nonalcoholic steatohepatitis which is a more severe form of liver disease characterized by inflammation and fibrosis. Further progression leads to cirrhosis, which predisposes patients to hepatocellular carcinoma or liver failure. The mechanism by which simple steatosis progresses to steatohepatitis is not entirely clear. However, multiple pathways have been proposed. A common link amongst many of these pathways is disruption of the homeostasis of bile acids. Other than aiding in the absorption of lipids and lipid-soluble vitamins, bile acids act as ligands. For example, they bind to farnesoid X receptor, which is critically involved in many of the pathways responsible for maintaining bile acid, glucose, and lipid homeostasis. Alterations to these pathways can lead to dysregulation of energy balance and increased inflammation and fibrosis. Repeated insults over time may be the key to development of steatohepatitis. For this reason, current drug therapies target aspects of these pathways to try to reduce and halt inflammation and fibrosis. This review will focus on the role of bile acids in these various pathways and how changes in these pathways may result in steatohepatitis. While there is no approved pharmaceutical treatment for either hepatic steatosis or steatohepatitis, this review will also touch upon the multitude of potential therapies.

Introduction

Nonalcoholic fatty liver disease (NAFLD) is growing in prevalence worldwide. Currently, it is reported to affect about 30% of the population in the United States (Younossi et al., 2016). Yet, prevalence is likely higher than reported since NAFLD is asymptomatic and requires a tissue biopsy for diagnosis. Prevalence is also increasing in adolescents and children, with approximately 10–20% of this population affected (Temple et al., 2016). NAFLD is a spectrum of diseases ranging from simple steatosis, nonalcoholic steatohepatitis (NASH), and fibrosis. Simple steatosis can progress into NASH, which is a more severe form of liver disease marked by the presence of hepatocyte ballooning and inflammation. The prevalence of NASH in the developed world is at least 2–3% (Satapathy and Sanyal, 2015). About 30% of patients with NAFLD are estimated to develop NASH (Younossi et al., 2016). The mechanism by which this occurs is not well known. NASH can subsequently progress into liver cirrhosis and hepatocellular carcinoma (HCC). Currently, the second most common indication for liver transplants in the United States is HCC secondary to NASH but this is expected to become the number one indication in the near future (Wong et al., 2014).

Due to the growing prevalence of NAFLD, there will be an inevitable increase in the prevalence of NASH, liver cirrhosis, and HCC. Except for life style modification, no therapies exist to halt or reverse NAFLD or NASH. However, there is a lot of interest in discovering such treatments, since curing patients of NAFLD would not only prevent NASH-associated HCC, but it would also improve the multitude of comorbidities often associated with NAFLD. NAFLD and NASH often occur in conjunction with obesity, hypertension, dyslipidemia, and insulin resistance. Patients with NAFLD or NASH are also at increased risk of cardiovascular disease. Thus, understanding the mechanism behind the progression of NAFLD to NASH is crucial as this would offer some insights into potential targets for the development of drug therapies that can successfully reverse or halt NAFLD progression.

Bile acids (BAs) are well known for their role in fat absorption (Hofmann, 1963). However, they also act as signaling molecules involved in a variety of pathways that regulate BA, glucose, and lipid homeostasis (Patti et al., 2009, Qi et al., 2015, Watanabe et al., 2011). For this reason, pathways linked to BAs have been implicated as targets for NAFLD and NASH drug therapies. While several drugs have been developed, their success has been variable and further research still needs to be done to develop better, more reliable therapies.

Section snippets

NAFLD and NASH

Obesity predisposes individuals to the development of a fatty liver. With obesity on the rise, it is not surprising that NAFLD is becoming more prevalent. NAFLD, however, can develop in patients with normal or lean body weights. NAFLD is defined by the presence of macrovesicular fat accumulation in more than 5% of hepatocytes in patients who consume less than 20 grams of alcohol per day (Yuan and Bambha, 2015). Alterations in lipid metabolism that ultimately lead to increased fat accumulation

BA synthesis

BAs are amphipathic molecules synthesized from cholesterol in the liver and are a component of bile. Bile is stored in the gallbladder and upon food consumption, released into the duodenum in response to cholecystokinin (CCK), a peptide hormone synthesized in enteroendocrine cells of the duodenum. BAs aid in lipid emulsification and absorption of fat and fat-soluble vitamins.

BAs are synthesized via one of two pathways: the classical pathway (or neutral pathway) and the alternative pathway (or

BA transport

After BAs are synthesized, they are exported into the gallbladder and secreted into the duodenum. Most are recirculated back to the liver from the terminal ileum. The remainder enter the colon where some are reabsorbed back into the liver while others are excreted. This enterohepatic circulation of BAs involves multiple transporters (Fig. 1). These transporters are important to note since they are potential targets for therapeutic interventions. Briefly, BAs are actively transported from

Nuclear hormone receptors

BA regulation of other pathways occurs through BA binding and mainly activation of nuclear hormone receptors (NHR), such as farnesoid X receptor (FXR), vitamin D receptor (VDR), and pregnane X receptor (PXR) (Guo et al., 2003, Makishima et al., 1999, Makishima et al., 2002). Activation of these NHRs as transcription factors requires that they interact with retinoid X receptor (RXR) as a heterodimer (Lu et al., 2000). They then act on various regulatory regions of genes to up- and down-regulate

BAs and glucose metabolism

BAs help regulate glucose metabolism via FXR and TGR5, but the mechanism by which this occurs is still unclear, as studies have shown dissimilar results. BA activation of TGR5 results in increased secretion of GLP-1 and decreased insulin resistance in obese mice (Thomas et al., 2009). FXR decreases hepatic gluconeogenesis, glycolysis, and increases glycogen synthesis (Jiao et al., 2015). Type II diabetes is associated with increased gluconeogenesis and, therefore, BAs, via FXR, may play a role

BAs and NAFLD/NASH

BAs have emerged as a therapeutic target for NAFLD prevention and/or treatment. Alterations in both total BA levels and composition have been noted in both rodents and humans with NAFLD/NASH (Aranha et al., 2008, Lake et al., 2013, Tanaka et al., 2012). Livers from rats fed a HFD were found to have higher glycine-conjugated BAs rather than taurine-conjugated BAs (Jia et al., 2014). Further, the total glycine-conjugated BA level positively correlated with macrovesicular steatosis score (Jia

Current therapies

To date, no medications can reverse NAFLD or NASH. Again, understanding the mechanism behind NAFLD progression is an important step towards development of pharmaceutical therapies. BAs regulate multiple pathways that likely play important roles in NAFLD progression. Thus, there are various targets for drugs (Fig. 2). However, as one can imagine, there is an intricate interplay among the different pathways to maintain BA, lipid, and glucose homeostasis and a disruption in one pathway may lead to

BAs and microbiota

Bacteria in the distal small bowel and colon break BAs down into secondary BAs, the main ones being DCA and LCA. Thus, gut microbiota can alter BA composition and affect BA metabolism. Results to date have been extensively reviewed (Bashiardes et al., 2016, He et al., 2016, Mouzaki et al., 2013, Mouzaki et al., 2016) and will only be briefly discussed here. One study looked at the role of intestinal FXR on NAFLD and found an increased level of tauro-β-muricholic acid (T-β-MCA) in the ileum in

Conclusion

BAs are involved in multiple pathways to regulate BA, glucose, and lipid metabolism. As discussed, many of these pathways involve BAs acting on FXR and TGR5, as well as other signaling pathways. Changes in BA levels and composition, via alterations in BA receptors, negative and positive feedback mechanisms, and even gut microbiota, therefore can affect other systems. These pathways are intricately involved with one another such that an alteration in one changes the others to maintain a

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