Proceedings of the National Academy of Sciences - PNAS, 2019-07, Vol.116 (30), p.15184-15193
2019
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- Autor(en) / Beteiligte
- Titel
- YIPF6 controls sorting of FGF21 into COPII vesicles and promotes obesity
- Ist Teil von
- Proceedings of the National Academy of Sciences - PNAS, 2019-07, Vol.116 (30), p.15184-15193
- Ort / Verlag
- United States: National Academy of Sciences
- Erscheinungsjahr
- 2019
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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]; Yipf6KLZ/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 Yipf6KLZ/Y mice secrete more FGF21 than hepatocytes from wild-type mice. Consequently, Yipf6KLZ/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. Yipf6KLZ/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 inverselywith levels of FGF21 in serumfrom patientswith 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0027-8424eISSN: 1091-6490DOI: 10.1073/pnas.1904360116Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6660779
- Format
- –
- Schlagworte
- Animals, Biological Sciences, Body Temperature, Coat protein, COP-Coated Vesicles - genetics, COP-Coated Vesicles - metabolism, Diet, Diet, High-Fat - adverse effects, Endoplasmic reticulum, Endoplasmic Reticulum - genetics, Endoplasmic Reticulum - metabolism, Energy balance, Energy expenditure, Energy Metabolism - genetics, Fatty liver, Fibroblast growth factors, Fibroblast Growth Factors - blood, Fibroblast Growth Factors - genetics, Gene expression, Gene Expression Regulation, Growth factors, Hepatocytes, Hepatocytes - metabolism, Hepatocytes - pathology, High fat diet, Homeostasis, Humans, Lipids, Lipolysis, Lipolysis - genetics, Liver, Liver - metabolism, Liver - pathology, Liver diseases, Membrane Proteins - genetics, Membrane Proteins - metabolism, Metabolic disorders, Metabolic syndrome, Metabolic Syndrome - etiology, Metabolic Syndrome - genetics, Metabolic Syndrome - metabolism, Metabolic Syndrome - pathology, Mice, Mice, Knockout, Mutation, Non-alcoholic Fatty Liver Disease - genetics, Non-alcoholic Fatty Liver Disease - metabolism, Non-alcoholic Fatty Liver Disease - pathology, Obesity, Obesity - etiology, Obesity - genetics, Obesity - metabolism, Obesity - pathology, Packaging, Plasma levels, PNAS Plus, Protein Binding, Proteins, Secretion, Signal Transduction, Steatosis, Thermogenesis, Thermogenesis - genetics, Vesicles, Vesicular Transport Proteins - genetics, Vesicular Transport Proteins - metabolism