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.
Highlights
Hepatic very low density lipoprotein (VLDL) overproduction is a characteristic feature of diabetes and an important contributor to diabetic dyslipidemia
Diabetes, and hepatic steatosis are associated with altered hepatic sortilin 1 (Sort1), we first measured liver Sort1 expression in genetic obese ob/ob mice
Results from this study suggests that free fatty acids (FFA)-mediated posttranslational downregulation of hepatic Sort1 may promote the development and progression of diabetic dyslipidemia, the underlying cause of increased cardiovascular disease (CVD) risk among obese and diabetic patients
Summary
Hepatic VLDL overproduction is a characteristic feature of diabetes and an important contributor to diabetic dyslipidemia. Mechanistic studies showed that the saturated fatty acid palmitate activated extracellular signal-regulated kinase (ERK) and inhibited Sort protein by mechanisms involving Sort protein ubiquitination and degradation. Hepatic ERK signaling was activated in diabetic mice, whereas blocking ERK signaling by an ERK inhibitor increased hepatic Sort protein in mice These results suggest that increased saturated fatty acids downregulate liver Sort protein, which may contribute to the development of dyslipidemia in obesity and diabetes.—Bi, L., J. Mechanistic studies in mice suggest that liver Sort may reduce plasma LDL-C via modulating apoB metabolism: first, intracellular Sort recognizes apoB as a ligand and directs newly synthesized apoB for lysosomal degradation, leading to reduced hepatic apoB secretion; second, cell surface Sort may facilitate extracellular apoB-containing LDL internalization for subsequent lysosomal degradation [12, 14, 15]
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