Hepatic DKK1-driven steatosis is CD36 dependent

Life Sci Alliance. 2022 Nov 21;6(1):e202201665. doi: 10.26508/lsa.202201665. Print 2023 Jan.

Abstract

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 approaches, 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-PPARγ-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.

MeSH terms

  • CD36 Antigens / metabolism
  • Diet, High-Fat
  • Hepatocytes
  • Humans
  • Intercellular Signaling Peptides and Proteins
  • Lipid Metabolism / genetics
  • Liver Cirrhosis
  • Non-alcoholic Fatty Liver Disease* / genetics

Substances

  • DKK1 protein, human
  • Intercellular Signaling Peptides and Proteins
  • CD36 Antigens