title: Saturated fatty acids activate ERK signaling to downregulate hepatic sortilin 1 in obese and diabetic mice.
abstract: Hepatic VLDL overproduction is a characteristic feature of diabetes and an important contributor to diabetic dyslipidemia. Hepatic sortilin 1 (Sort1), a cellular trafficking receptor, is a novel regulator of plasma lipid metabolism and reduces plasma cholesterol and triglycerides by inhibiting hepatic apolipoprotein B production. Elevated circulating free fatty acids play key roles in hepatic VLDL overproduction and the development of dyslipidemia. This study investigated the regulation of hepatic Sort1 in obesity and diabetes and the potential implications in diabetic dyslipidemia. Results showed that hepatic Sort1 protein was markedly decreased in mouse models of type I and type II diabetes and in human individuals with obesity and liver steatosis, whereas increasing hepatic Sort1 expression reduced plasma cholesterol and triglycerides in mice. Mechanistic studies showed that the saturated fatty acid palmitate activated extracellular signal-regulated kinase (ERK) and inhibited Sort1 protein by mechanisms involving Sort1 protein ubiquitination and degradation. Consistently, hepatic ERK signaling was activated in diabetic mice, whereas blocking ERK signaling by an ERK inhibitor increased hepatic Sort1 protein in mice. These results suggest that increased saturated fatty acids downregulate liver Sort1 protein, which may contribute to the development of dyslipidemia in obesity and diabetes.
authors.affiliation: Department of Pharmacology, Toxicology, and Therapeutics and Liver Center, University of Kansas Medical Center, Kansas City, KS 66160; and.
authors.forename: Lipeng
authors.initials: L
authors.lastname: Bi
authors.forename: John Y L
authors.initials: JY
authors.lastname: Chiang
authors.forename: Wen-Xing
authors.initials: WX
authors.lastname: Ding
authors.forename: Winston
authors.initials: W
authors.lastname: Dunn
authors.forename: Benjamin
authors.initials: B
authors.lastname: Roberts
authors.forename: Tiangang
authors.initials: T
authors.lastname: Li
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D015536:Down-Regulation; D050171:Dyslipidemias / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000502:physiology*; D005234:Fatty Liver / Q000378:metabolism; D005786:Gene Expression Regulation; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000378:metabolism*; D019308:Palmitic Acid / Q000494:pharmacology; D059748:Proteolysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000099183:Sortilin
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D005230:Fatty Acids, Nonesterified; D019308:Palmitic Acid; D012333:RNA, Messenger; D000099183:Sortilin
keywords: diabetes; extracellular signal-regulated kinase; fatty liver; lipid metabolism; mitogen-activated protein kinase; obesity
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