Milk Fat Globule-Epidermal Growth Factor-Factor 8 Improves Hepatic Steatosis and Inflammation

Hepatology. 2021 Feb;73(2):586-605. doi: 10.1002/hep.31277. Epub 2020 Nov 20.

Abstract

Background and aims: Milk fat globule-epidermal growth factor-factor 8 (MFGE8) has been shown to be a critical extracellular molecule that mediates apoptotic signaling in the pathological process of nonalcoholic fatty liver disease (NAFLD). MFGE8 is abundantly expressed in hepatocytes, but its function in the pathogenesis of NAFLD has not been characterized.

Approach and results: In our current study, hepatic MFGE8 showed a protective role in the pathogenesis of NAFLD. Hepatic MFGE8 deletion largely exacerbated lipid accumulation and inflammatory responses in the liver in response to overnutrition. Mechanistically, intercellular MFGE8 was shown to directly bind to apoptosis signal-regulating kinase 1 (ASK1) and to inhibit its dimerization and phosphorylation under a normal diet. However, under metabolic challenges, decreased cytoplasmic MFGE8 facilitated the dimerization and phosphorylation of ASK1 and subsequent mitogen-activated protein kinase signaling in hepatocytes.

Conclusions: Hepatic MFGE8 is an endogenous inhibitor that halts the progression of hepatic steatosis and inflammation. Metabolic challenge-induced loss of intracellular MFGE8 facilitates ASK1 dimerization and phosphorylation. Therefore, maintaining hepatic MFGE8 levels may serve as an alternative strategy for the treatment of NAFLD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Surface / genetics
  • Antigens, Surface / metabolism*
  • Diet, High-Fat / adverse effects
  • Disease Models, Animal
  • Hepatocytes
  • Humans
  • Lipid Metabolism / immunology
  • Liver / immunology
  • Liver / pathology*
  • MAP Kinase Kinase Kinase 5 / metabolism
  • MAP Kinase Signaling System / immunology
  • Male
  • Mice
  • Mice, Knockout
  • Milk Proteins / genetics
  • Milk Proteins / metabolism*
  • Non-alcoholic Fatty Liver Disease / immunology*
  • Non-alcoholic Fatty Liver Disease / pathology
  • Phosphorylation / immunology
  • Protein Multimerization / immunology

Substances

  • Antigens, Surface
  • Mfge8 protein, mouse
  • Milk Proteins
  • MAP Kinase Kinase Kinase 5
  • Map3k5 protein, mouse