Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis

“…the cause of steatosis, and not the fat accumulation by itself, produces cirrhosis”—Heribert Thaler, 19751 W ith nonalcoholic steatohepatitis (NASH), NASH cirrhosis, and NASH-related hepatocellular carcinoma becoming increasingly prevalent, the need for effective therapies has never been greater. Unfortunately, our understanding of what causes NASH at the molecular level remains mostly speculative, and thus our ability to design clinical trials that test rationally designed therapies is limited. More than a decade has passed since Christopher Day and Oliver James first proposed the oft-cited two-hit hypothesis of nonalcoholic fatty liver disease (NAFLD) to explain the pathogenesis of NASH.2, 3 According to…