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

YIPF6 controls sorting of FGF21 into COPII vesicles and promotes obesity.

Author information

1
School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, 211198 Nanjing, Jiang Su, China; wanglirui@cpu.edu.cn bruce.beutler@UTSouthwestern.edu beschnabl@ucsd.edu.
2
Department of Medicine, University of California San Diego, La Jolla, CA 92093.
3
Department of Medicine, VA San Diego Healthcare System, San Diego, CA 92161.
4
School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, 211198 Nanjing, Jiang Su, China.
5
Department of Hepatology, Beijing Ditan Hospital, Capital Medical University, Chaoyang District, 100015 Beijing, China.
6
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093.
7
School of Traditional Chinese Pharmacy, China Pharmaceutical University, 211198 Nanjing, Jiang Su, China.
8
Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037.
9
Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, CA 92037.
10
Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390 wanglirui@cpu.edu.cn bruce.beutler@UTSouthwestern.edu beschnabl@ucsd.edu.
11
Department of Medicine, University of California San Diego, La Jolla, CA 92093; wanglirui@cpu.edu.cn bruce.beutler@UTSouthwestern.edu beschnabl@ucsd.edu.

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

PMID:
31289229
PMCID:
PMC6660779
[Available on 2020-01-09]
DOI:
10.1073/pnas.1904360116

Conflict of interest statement

Conflict of interest statement: B.B. received salary support from Pfizer, Inc. B.S. is consulting for Ferring Research Institute.

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