Targeting bile acids and lipotoxicity for NASH treatment

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, affecting approximately 20%-30% of the population in Western countries. Nonalcoholic steatohepatitis (NASH) is the progressive form of NAFLD that can develop into cirrhosis and hepatocellular carcinoma (HCC). However, the underlying mechanism of progression of steatosis to NASH and cirrhosis is poorly understood. Multiple factors, including insulin resistance, inflammation, oxidative stress, lipotoxicity, and bile acid toxicity, have been implicated in NASH progression. The bile acid-activated receptors farnesoid X receptor (FXR) and G-protein bile acid receptor-1 are metabolic integrators that function in the regulation of hepatic metabolism and homeostasis. Bile acids are derived from cholesterol in the liver and are secreted into the gastrointestinal system for nutrient absorption. The gut-to-liver axis plays a critical role in the regulation of bile acid synthesis and homeostasis. In the intestine, bile acids activate FXR to induce fibroblast growth factor 15 (FGF15) in mice or FGF19 in humans (Fig. 1). FGF15 and FGF19 are secreted into portal circulation to activate the hepatic FGF receptor 4/b-Klotho complex, which inhibits cholesterol 7a-hydroxylase (CYP7A1), the key regulatory enzyme in bile acid synthesis. Activation of FXR by bile acids and FXR agonists has been shown to reduce hepatic lipogenesis and improve glucose tolerance and insulin resistance in diet-induced obese mouse models. Bile acid derivatives that activate FXR have been developed as therapeutic drugs for treating cholestatic liver diseases and NASH. A synthetic bile acid, obeticholic acid, has been approved by the U.S. Food and Drug Administration for primary biliary cirrhosis, and currently patients are being recruited for phase 3 of clinical trials for NASH fibrosis. Synthetic bile acids are safe and devoid of side effects but have inherent problems for bile acids, including pruritus and reducing serum high-density lipoprotein cholesterol levels. Nonbile acid-based drugs, such as FGF19, have been developed for treating chronic liver disease (http://www. clinicaltrials.gov, NCT02443116). FGF19 is a postprandial insulin-independent activator of hepatic protein and glycogen synthesis. The hepatic response to FGF19 is impaired in NAFLD patients with insulin resistance, and fasting FGF19 levels are reduced in NAFLD patients. FGF19 has been shown to stimulate energy metabolism and reduces steatosis by reducing fatty acid synthesis, increasing fatty acid oxidation, and stimulating adipose tissue browning. However, the underlying mechanism of how FGF19 protects against bile acid-induced liver injury and inflammation is not clear and requires further study. As a growth factor, FGF19 has tumorigenic activity. FGF19 transgenic mice have been shown to develop HCC. To eliminate the tumorigenic activity, an FGF19 variant, M70, has been shown to inhibit Abbreviations: AAV, adeno-associated virus; CYP7A1, cholesterol 7a-hydroxylase; FGF15, fibroblast growth factor in mice; FGF19, fibroblast growth factor in humans; FXR, farnesoid X receptor; HCC, hepatocellular carcinoma; HFFCD, high-fat, high-fructose, high-cholesterol diet; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis.