RESUMEN
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 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.
Asunto(s)
Factores de Crecimiento de Fibroblastos/genética , Hígado/metabolismo , Proteínas de la Membrana/genética , Síndrome Metabólico/genética , Enfermedad del Hígado Graso no Alcohólico/genética , Obesidad/genética , Animales , Temperatura Corporal , Vesículas Cubiertas por Proteínas de Revestimiento/genética , Vesículas Cubiertas por Proteínas de Revestimiento/metabolismo , Dieta Alta en Grasa/efectos adversos , Retículo Endoplásmico/genética , Retículo Endoplásmico/metabolismo , Metabolismo Energético/genética , Factores de Crecimiento de Fibroblastos/sangre , Regulación de la Expresión Génica , Hepatocitos/metabolismo , Hepatocitos/patología , Humanos , Lipólisis/genética , Hígado/patología , Proteínas de la Membrana/metabolismo , Síndrome Metabólico/etiología , Síndrome Metabólico/metabolismo , Síndrome Metabólico/patología , Ratones , Ratones Noqueados , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Obesidad/etiología , Obesidad/metabolismo , Obesidad/patología , Unión Proteica , Transducción de Señal , Termogénesis/genética , Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/metabolismoRESUMEN
A major challenge for the human body is to maintain symbiotic relationships with bacterial communities that colonize their intestines. Although several molecules important for intestinal homeostasis have been discovered, the vast array still needs to be identified. We approached this task using a forward genetic approach, which revealed several molecules essential for intestinal homeostasis. One recently identified molecule is Ypt1p-interacting protein 1 domain family, member 6 (Yipf6). Mice with a null mutation in Yipf6 are hypersensitive to dextran sulfate sodium (DSS) induced colitis and develop spontaneous intestinal inflammation. Members of the Yip1 family are believed to be involved in ER to Golgi membrane transport. In this review we summarize recent advances in the understanding of genes involved in intestinal homeostasis with a specific focus on the Yip family members. We speculate on how deficiency or dysfunction of Yip molecules may dysregulate intestinal homeostasis leading to pathogenic states.