This article is available online at http://www.jlr.org lipoprotein (HDL), and abnormal low density lipoprotein (LDL) metabolism, which signifi cantly increases the risk of cardiovascular disease (CVD), the leading cause of morbidity and mortality in type II diabetes ( 1 ). Increased hepatic very low density lipoprotein (VLDL)/apolipoprotein B (apoB) secretion is a characteristic feature of type II diabetes and a major cause of diabetic dyslipidemia ( 2, 3 ), but molecular mechanisms linking diabetes to hepatic apoB overproduction are only partially understood. In obesity and diabetes, circulating free fatty acids (FFA) are often elevated mainly due to abnormal adipocyte lipolysis ( 3 ). Recent studies showed that elevated plasma and tissue FFAs are critically involved in the development of hyperlipidemia. Current evidence supports that circulating FFA level is an important CVD risk factor in diabetes ( 4, 5 ). In addition, metabolic profi ling studies also showed that the abundant saturated fatty acid palmitate in the plasma is a reliable biomarker for type II diabetes ( 6 ). At the molecular level, increased hepatic FFA uptake provides substrates for hepatic triglyceride synthesis, leading to apoB lipidation and VLDL synthesis and secretion. In addition, elevated FFAs and their lipid intermediates, namely, ceramides and diacylglycerols, cause abnormal activation of protein kinase C (PKC) isoforms and mitogen-activated protein kinases (MAPK), which results in infl ammation and insulin resistance ( 7,8 ). Although it is well known that activation of infl ammatory signaling and impairment of insulin signaling contribute signifi cantly to apoB overproduction and hyperlipidemia in diabetes, the downstream mechanisms are still not fully clear ( 9, 10 ).Abstract Hepatic VLDL overproduction is a characteristic feature of diabetes and an important contributor to diabetic dyslipidemia. Hepatic sortilin 1 (Sort1), a cellular traffi cking 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 satu...

Background: Hepatic sortilin 1 inhibits apoB secretion and lowers plasma lipids. Results: Fish oil and fenofibrate treatments prevented fatty acid-induced hepatic Sort1 posttranslational down-regulation in Western diet-fed mice. Conclusion: Hepatic Sort1 is an in vivo target of n-3 PUFAs and fenofibrate. Significance: Increasing hepatic Sort1 by therapeutic approaches may improve plasma lipid homeostasis.