YIPF6 controls sorting of FGF21 into COPII vesicles and promotes obesity

Proc Natl Acad Sci U S A. 2019 Jul 23;116(30):15184-15193. doi: 10.1073/pnas.1904360116. Epub 2019 Jul 9.

Abstract

Fibroblast growth factor 21 (FGF21) is an endocrine hormone that regulates glucose, lipid, and energy homeostasis. While gene expression of FGF21 is regulated by the nuclear hormone receptor peroxisome proliferator-activated receptor alpha in the fasted state, little is known about the regulation of trafficking and secretion of FGF21. We show that mice with a mutation in the Yip1 domain family, member 6 gene (Klein-Zschocher [KLZ]; Yipf6 KLZ/Y ) on a high-fat diet (HFD) have higher plasma levels of FGF21 than mice that do not carry this mutation (controls) and hepatocytes from Yipf6 KLZ/Y mice secrete more FGF21 than hepatocytes from wild-type mice. Consequently, Yipf6 KLZ/Y mice are resistant to HFD-induced features of the metabolic syndrome and have increased lipolysis, energy expenditure, and thermogenesis, with an increase in core body temperature. Yipf6 KLZ/Y mice with hepatocyte-specific deletion of FGF21 were no longer protected from diet-induced obesity. We show that YIPF6 binds FGF21 in the endoplasmic reticulum to limit its secretion and specifies packaging of FGF21 into coat protein complex II (COPII) vesicles during development of obesity in mice. Levels of YIPF6 protein in human liver correlate with hepatic steatosis and correlate inversely with levels of FGF21 in serum from patients with nonalcoholic fatty liver disease (NAFLD). YIPF6 is therefore a newly identified regulator of FGF21 secretion during development of obesity and could be a target for treatment of obesity and NAFLD.

Keywords: COPII vesicles; FGF21; YIPF6; obesity; sorting receptor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Body Temperature
  • COP-Coated Vesicles / genetics
  • COP-Coated Vesicles / metabolism
  • Diet, High-Fat / adverse effects
  • Endoplasmic Reticulum / genetics
  • Endoplasmic Reticulum / metabolism
  • Energy Metabolism / genetics
  • Fibroblast Growth Factors / blood
  • Fibroblast Growth Factors / genetics*
  • Gene Expression Regulation
  • Hepatocytes / metabolism
  • Hepatocytes / pathology
  • Humans
  • Lipolysis / genetics
  • Liver / metabolism*
  • Liver / pathology
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Metabolic Syndrome / etiology
  • Metabolic Syndrome / genetics*
  • Metabolic Syndrome / metabolism
  • Metabolic Syndrome / pathology
  • Mice
  • Mice, Knockout
  • Non-alcoholic Fatty Liver Disease / genetics*
  • Non-alcoholic Fatty Liver Disease / metabolism
  • Non-alcoholic Fatty Liver Disease / pathology
  • Obesity / etiology
  • Obesity / genetics*
  • Obesity / metabolism
  • Obesity / pathology
  • Protein Binding
  • Signal Transduction
  • Thermogenesis / genetics
  • Vesicular Transport Proteins / genetics
  • Vesicular Transport Proteins / metabolism

Substances

  • Membrane Proteins
  • Vesicular Transport Proteins
  • YIPF6 protein, human
  • Yipf6 protein, mouse
  • fibroblast growth factor 21
  • Fibroblast Growth Factors