PAS Kinase Drives Lipogenesis through SREBP-1 Maturation
| Autor: | Hana Sabic, Jeremy Blitzer, Xiaoying Wu, Wojciech I. Swiatek, Jared Rutter, John Mckearn, Ben S. Zweifel, Irene Dorweiler, Donna L. Romero, G. Allen Nickols, Chintan K. Kikani |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Male
medicine.medical_specialty medicine.medical_treatment Protein Serine-Threonine Kinases Carbohydrate metabolism Article General Biochemistry Genetics and Molecular Biology Rats Sprague-Dawley Mice Insulin resistance Internal medicine medicine Animals Humans Obesity lcsh:QH301-705.5 Protein Kinase Inhibitors Transcription factor Cells Cultured Dyslipidemias biology Lipogenesis Insulin Hep G2 Cells medicine.disease Rats Sterol regulatory element-binding protein Insulin receptor HEK293 Cells Endocrinology lcsh:Biology (General) Hepatocytes biology.protein Metabolic syndrome Sterol Regulatory Element Binding Protein 1 |
| Zdroj: | Cell Reports, Vol 8, Iss 1, Pp 242-255 (2014) |
| ISSN: | 2211-1247 |
| DOI: | 10.1016/j.celrep.2014.06.006 |
| Popis: | SummaryElevated hepatic synthesis of fatty acids and triglycerides, driven by hyperactivation of the SREBP-1c transcription factor, has been implicated as a causal feature of metabolic syndrome. SREBP-1c activation requires the proteolytic maturation of the endoplasmic-reticulum-bound precursor to the active, nuclear transcription factor, which is stimulated by feeding and insulin signaling. Here, we show that feeding and insulin stimulate the hepatic expression of PASK. We also demonstrate, using genetic and pharmacological approaches, that PASK is required for the proteolytic maturation of SREBP-1c in cultured cells and in the mouse and rat liver. Inhibition of PASK improves lipid and glucose metabolism in dietary animal models of obesity and dyslipidemia. Administration of a PASK inhibitor decreases hepatic expression of lipogenic SREBP-1c target genes, decreases serum triglycerides, and partially reverses insulin resistance. While the signaling network that controls SREBP-1c activation is complex, we propose that PASK is an important component with therapeutic potential. |
| Databáze: | OpenAIRE |
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