Hepatic DKK1-driven steatosis is CD36 dependent

Nonalcoholic fatty liver disease (NAFLD) is prevalent worldwide; about 25% of NAFLD silently progress into steatohepatitis, in which some of them may develop into fibrosis, cirrhosis and liver failure. However, few drugs are available for NAFLD, partly because of an incomplete understanding of its pathogenic mechanisms. Here, using in vivo and in vitro gain-and loss-of-function ap-proaches, we identified up-regulated DKK1 plays a pivotal role in high-fat diet-induced NAFLD and its progression. Mechanistic analysis reveals that DKK1 enhances the capacity of hepatocytes to uptake fatty acids through the ERK-PPAR gamma-CD36 axis. Moreover, DKK1 increased insulin resistance by activating the JNK signaling, which in turn exacerbates disorders of hepatic lipid metabolism. Our finding suggests that DKK1 may be a potential therapeutic and diagnosis candidate for NAFLD and metabolic disorder progression.

Automated summary

Nonalcoholic fatty liver disease (NAFLD) is a prevalent global disease with about 25% of patients progressing to severe conditions. Up-regulated DKK1 plays a pivotal role in the development and progression of NAFLD induced by high-fat diet, making it a potential therapeutic and diagnostic target.