Metabolic Targets in Nonalcoholic Fatty Liver Disease

Abstract

The prevalence and diagnosis of nonalcoholic fatty liver disease (NAFLD) is on the rise worldwide and currently has no FDA-approved pharmacotherapy. The increase in disease burden of NAFLD and a more severe form of this progressive liver disease, nonalcoholic steatohepatitis (NASH), largely mirrors the increase in obesity and type 2 diabetes (T2D) and reflects the hepatic manifestation of an altered metabolic state. Indeed, metabolic syndrome, defined as a constellation of obesity, insulin resistance, hyperglycemia, dyslipidemia and hypertension, is the major risk factor predisposing the NAFLD and NASH. There are multiple potential pharmacologic strategies to rebalance aspects of disordered metabolism in NAFLD. These include therapies aimed at reducing hepatic steatosis by directly modulating lipid metabolism within the liver, inhibiting fructose metabolism, altering delivery of free fatty acids from the adipose to the liver by targeting insulin resistance and/or adipose metabolism, modulating glycemia, and altering pleiotropic metabolic pathways simultaneously. Emerging data from human genetics also supports a role for metabolic drivers in NAFLD and risk for progression to NASH. In this review, we highlight the prominent metabolic drivers of NAFLD pathogenesis and discuss the major metabolic targets of NASH pharmacotherapy.

Figure 1

Model of hepatic lipid metabolism, inflammation, and fibrosis. Hepatic lipid content is a balance between uptake and synthesis of lipids and lipid disposal/export. The primary source of hepatic fat is the liberation of free fatty acids from adipose/fat tissue via lipolysis (A),, , with additional uptake of fatty acids from the circulation (B) and de novo lipogenesis (D). Lipids are cleared from the liver by beta-oxidation of fatty acids in the mitochondria (C) and through export as very low-density lipoprotein (VLDL) particles. Excess hepatic lipid accumulation, on its own or in combination with additional environmental insults, can trigger an inflammatory response in the liver characterized histologically as hepatocyte ballooning (E). Ultimately, the hepatic inflammatory response drives NASH disease progression as it promotes activation of hepatic stellate cells (HSC) and fibrosis (F).