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

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.

Keywords: Bile acids; Enterohepatic circulation; Farnesoid X receptor (FXR); Gut-liver crosstalk; Nonalcoholic fatty liver disease (NAFLD); Nonalcoholic steatohepatitis (NASH).

Figure 1. Enterohepatic circulation of BAs

BAs are produced from cholesterol, enter bile canaliculi via BSEP and MRP2, empty into the duodenum upon stimulation of the gallbladder with CCK, get mostly reabsorbed in the terminal ileum via ASBT, then shuttled into the portal vein via OSTα/β where they are recycled back to the hepatocyte. Gut microbiota deconjugate BAs into LCA and DCA. LCA is insoluble and excreted in feces but DCA can be reabsorbed into the portal vein and recycled. BAs act on FXR in the liver to induce SHP to downregulate gene expression of CYP7A1/Cyp7a1 and CYP8A1/Cyp8b1. BAs also downregulate their own synthesis via a SHP-independent pathway involving FGF15 (FGF19 in humans) produced in the ileum. FGF15 leads to phosphorylation of FGFR4, which then activates ERK1/2 pathways to downregulate gene expression of CYP7A1/Cyp7a1 and CYP8B1/Cyp8b1. FGFR4 requires a cofactor, βklotho, to function. Green arrows indicate upregulation or stimulation. Red lines indicate downregulation. Broken arrows indicate that multiple steps are involved but not depicted.

Figure 2. Potential pathways of NAFLD and NASH development and therapeutic targets for NAFLD/NASH treatment

The exact mechanism for NAFLD development and progression to NASH is unknown. However, obesity and insulin resistance/diabetes are believed to be two significant contributing factors. Obesity leads to increased hepatic lipids, insulin resistance, cytokines in WAT, and changes in intestinal flora. Increased hepatic lipids results in increased oxidative stress and apoptosis. Insulin resistance can result in diabetes. Cytokines result in increased hepatic inflammation and with repeated insults, can lead to fibrosis. Changes in microbiota can cause changes in BA composition that can disrupt many pathways, since BAs are important regulators of lipid and glucose metabolism. BA conjugates and derivatives (such as OCA, UDCA, and TC-100) decrease hepatic gluconeogenesis and hepatic lipids. BA conjugates and derivatives can increase hepatic and intestinal FXR. Increased intestinal FXR can lead to increased FGF15/19 and increased FGFR4. BA binding resins (such as cholestyramine and colesevelam), are medications being used by patients with diabetes and despite having an opposite effect on BAs compared to BA conjugates, have been shown to help lower systemic lipids. However, they do not currently have a role in improving hepatic steatosis. Metformin, also used in patients with diabetes, decreases gluconeogenesis. FXR and TGR5 agonists have shown promising results with improvement in glucose tolerance and decrease in hepatic inflammation. ASBT inhibitors (such as SC-435 and 264W94) also show promising results, with decreased expression of SREBP1c and increased FXR (not depicted). Hepatic steatosis and glucose intolerance were demonstrated to be improved in rodent studies using ASBT inhibitors. Finally, bariatric surgery is emerging as another potential therapy for NAFLD and NASH. Bariatric surgery not only leads to weight loss, but has been shown to affect microbiota and improve insulin resistance independent of weight loss (not depicted).