Saturated Fatty Acids Activate Erk Signaling To Downregulate Hepatic Sortilin 1 In Obese And Diabetic Mice

Title

Saturated Fatty Acids Activate Erk Signaling To Downregulate Hepatic Sortilin 1 In Obese And Diabetic Mice

Creator

Bi L P; Chiang J Y L; Ding W X; Dunn W; Roberts B; Li T G

Publisher

Journal of Lipid Research

Date

2013
2013-10

Description

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.

Subject

apolipoprotein-b secretion; Biochemistry & Molecular Biology; cells; diabetes; extracellular signal-regulated kinase; fatty liver; function; induced insulin-resistance; ldl; lipid metabolism; liver; mitogen-activated protein kinase; obesity; overproduction; oxidative stress; ubiquitination; vascular; vldl production

Identifier

Format

Journal Article or Conference Abstract Publication

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Rights

Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).

Pages

2754-2762

Issue

10

Volume

54

Citation

Bi L P; Chiang J Y L; Ding W X; Dunn W; Roberts B; Li T G, “Saturated Fatty Acids Activate Erk Signaling To Downregulate Hepatic Sortilin 1 In Obese And Diabetic Mice,” NEOMED Bibliography Database, accessed January 24, 2021, https://neomed.omeka.net/items/show/9976.

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