Development of steatohepatitis in Ob/Ob mice is dependent on Toll-like receptor 4

The etiology of non-alcoholic fatty liver disease (NAFLD) progression, and why some patients develop non-alcoholic steatohepatitis (NASH) vs. uncomplicated NAFLD, is not well understood. Obesity and NAFLD are thought to be associated with high circulating levels of leptin; however, the role of leptin in NASH has been controversial. Secondly, as ob/ob mice are known to have elevated circulating levels of TLR4-stimulating endotoxin secondary to increased intestinal permeability.

We evaluated the long-term effects of steatosis on the livers of aleptinemic (OB) mice and the role of TLR4 in the development of hepatic sequelae in these animals.

At 20 weeks of age OB animals displayed grossly steatotic livers, but also features of early stage NASH including hepatocellular ballooning and numerous necroinflammatory foci with associated changes in serum aspartate aminotransferase (AST) and alanine transaminase (ALT). TLR4 KO did not affect the development of obesity or steatosis in ob/ob mice, but protected these animals from hepatitis and liver injury.

In conclusion, the data presented here indicate that steatohepatitis develops in the absence of leptin, and that TLR4 is integral to the development NASH secondary to hyperphagia.