PAS Kinase: roles in the regulation of hepatic lipid metabolism

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Title PAS Kinase: roles in the regulation of hepatic lipid metabolism
Publication Type dissertation
School or College School of Medicine
Department Biochemistry
Author Wu, Xiaoying
Date 2015-08
Description Excessive synthesis and storage of lipids is a prominent feature of the current epidemic of metabolic disorders, including obesity, diabetes and nonalcoholic fatty liver disease (NAFLD). Upon feeding, fatty acids and triglycerides are synthesized primarily in the liver in response to insulin signaling. This process is mediated by the sterol regulatory element binding protein 1c (SREBP-1c) transcription factor, a principal regulator of lipogenesis. Upon activation, SREBP- 1c stimulates the transcription of the key lipogenic enzymes that catalyze the synthesis of fatty acids and their esterification to triacylglycerides. Hyperactivation of SREBP-1c has been implicated in promoting pathologic fat synthesis and driving features of the metabolic syndrome, including hepatic lipid accumulation (steatosis), dyslipidemia and insulin resistance. PAS kinase (PASK) is an evolutionarily conserved serine/threonine kinase that has been proposed to function as a nutrient-responsive metabolic regulator. Pask-/- mice are resistant to high fat diet-induced metabolic disorders. Interestingly, Pask-/- mice exhibited almost complete protection from hepatic steatosis, but the mechanism underlying this phenotype was unknown. Here, we show that PASK promotes hepatic lipogenesis by activating SREBP-1c. This regulation occurs at the proteolytic maturation step of SREBP-1c, where the endoplasmic reticulum-bound precursor SREBP-1c undergoes proteolytic iv cleavages to liberate the transcriptionally active fragment of the protein. SREBP- 1c maturation is strongly induced by feeding and insulin signaling, a condition that also stimulates the hepatic expression of PASK. Using genetic and pharmacological approaches, we demonstrate that PASK is required for SREBP- 1c maturation in response to feeding and insulin stimulation. Inhibition of PASK results in decreased expression of the lipogenic SREBP-1c target genes and reduced lipid production in cultured cells and in the mouse and rat liver. Importantly, administration of a PASK inhibitor not only improves hepatic steatosis and whole-body dyslipidemia, but also partially reverses insulin resistance in animal models of diet-induced obesity and dyslipidemia, indicating that PASK is a potential therapeutic target for metabolic diseases. These studies not only further our understanding of the physiological functions of PASK, but also provide new insight into the pathogenesis and treatment of NAFLD and other metabolic disorders.
Type Text
Publisher University of Utah
Subject MESH Protein-Serine-Threonine Kinases; Adipose Tissue; Non-alcoholic Fatty Liver Disease; Diet, High-Fat; Metabolic Diseases; Diabetes Mellitus; Lipogenesis; Insulin Resistance; Fatty Liver; Lipid Metabolism Dyslipidemias; Esterification; Sterol Regulatory Element Binding Protein 1; Triglycerides; Protein Isoforms; Intracellular Signaling Peptides and Proteins
Dissertation Institution University of Utah
Dissertation Name Doctor of Philosophy
Language eng
Relation is Version of Digital version of PAS Kinase: Roles in the Regulation of Hepatic Lipid Metabolism
Rights Management Copyright © Xiaoying Wu 2015
Format application/pdf
Format Medium application/pdf
Format Extent 11,757,606 bytes
Source Original in Marriott Library Special Collections
ARK ark:/87278/s6jq4884
Setname ir_etd
ID 197362
Reference URL https://collections.lib.utah.edu/ark:/87278/s6jq4884
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