Targeting Metabolism, Insulin Resistance, and Diabetes to Treat Nonalcoholic Steatohepatitis

Abstract

Obesity, insulin resistance, and diabetes are strongly linked to the accumulation of excessive lipids in the liver parenchyma, a condition known as nonalcoholic fatty liver disease (NAFLD). Given its association with obesity and related metabolic diseases, it is not surprising that the prevalence of NAFLD has dramatically increased in the past few decades. NAFLD has become the most common liver disease in many areas of the world. The term, NAFLD, encompasses a spectrum of disorders that ranges from simple steatosis to steatosis with inflammatory lesions (nonalcoholic steatohepatitis [NASH]). Although simple steatosis might be relatively benign, epidemiologic studies have linked NASH to greatly increased risk of developing cirrhosis and hepatocellular carcinoma. Yet despite this, there are no approved treatments for the disease, and it remains a significant unmet medical need. This Perspective will review some of the relevant literature on the topic and examine approved and experimental NASH therapeutic concepts that target intermediary metabolism, insulin resistance, and diabetes to treat this emerging public health problem.

Figure 1

The histologic spectrum of NAFLD. Left: Steatosis without inflammation, hepatocyte ballooning, or fibrosis. Middle: Steatohepatitis with hepatocyte ballooning, Mallory-Denk bodies, lobular inflammation, and perisinusoidal fibrosis. Right: Cirrhosis with residual steatosis. Pictures were kindly provided by Dr. Elizabeth Brunt (Washington University School of Medicine in St. Louis).

Figure 2

Interactions between insulin resistance and NAFLD. Insulin resistance can promote NAFLD by leading to increased release of free fatty acids by adipose tissue and hyperglycemia/hyperinsulinemia, which promotes hepatic de novo lipogenesis. The contribution of dietary fat also cannot be discounted. Hepatic steatosis is also associated with developing/exacerbating systemic insulin resistance by direct and indirect mechanisms.

Figure 3

Investigational drugs for treating NASH. The proposed sites of action of various experimental NASH therapeutics are shown. Agonists for the PPARs, TRβ, and FXR nuclear receptors likely work by stimulating mitochondrial fatty acid oxidation. MPC inhibitors (MPCi) work by attenuating flux of pyruvate into mitochondrial pathways and likely stimulating fat oxidation. Inhibitors of various steps in de novo lipogenesis are also shown and include KHKi, ACCi, FASi, SCD1i, and DGATi. DAG, diacylglycerol; F-1-P, fructose-1-phosphate; FAO, fatty acid oxidation; TCA, tricarboxylic acid.