Rebuttal to: Inflammation: The Straw That Broke the NAFLD Liver!

See Point-Counterpoint articles on pages 1267 and 1273.

Nonalcoholic fatty liver disease (NAFLD) primarily begins with hepatosteatosis, resulting in hepatocellular damage, inflammation, and fibrosis. Although hepatosteatosis per se is well tolerated and protects from cellular damage, convincing evidence shows that lipotoxicity drives the progression of simple steatosis to nonalcoholic steatohepatitis (NASH). Although how hepatosteatosis causes lipotoxicity is incompletely defined, the concept of “fat accumulation and lipotoxicity are not synonymous” suggests that the type of fatty acids (quality) determines NASH progression in addition to quantity. For instance, the accumulation of saturated fatty acids because of an imbalance in the lipogenic and fatty acid oxidation pathways is linked with hepatic inflammation and insulin resistance and parallels NASH severity. Furthermore, the subpopulation of hepatocytes with high lipid content shows elevated markers of injury and inflammation. Thus, toxic lipids in the hepatocytes are sufficient to activate death receptors and damage-associated molecular pattern receptors, such as Toll-like receptor-4 leading to NASH progression.

We agree that that adipose tissue and gut participate in NAFLD progression by regulating the inflammatory pathways. However, it remains unclear whether the adipose tissue and gut bypass hepatosteatosis in promoting NAFLD progression. Under surplus energy and insulin-resistant states, lipotoxicity in the liver is induced by adipose tissue–derived free fatty acids. Similarly, short-chain fatty acids originating from gut microbial metabolism serve as substrates for hepatic lipogenesis. For example, toll-like receptor 5 (TLR5)-deficient mice, which exhibit a higher bacterial load, are more prone to develop microbiota-dependent hepatic lipid accumulation, insulin resistance, and inflammation. Mechanistically, TLR5-deficient mice display elevated oleate (C18:1) levels caused by a concomitant increase in hepatic lipids and SCD1 expression in the liver. Deleting hepatic SCD1 protects mice from hepatic steatosis and ameliorates hepatic insulin resistance and inflammation in TLR5-deficient mice. Thus, the extrahepatic factors promote NASH by modulating hepatosteatosis.