Liver-Specific Loss of Lipolysis-Stimulated Lipoprotein Receptor Triggers Systemic Hyperlipidemia in Mice

Abstract

OBJECTIVE-In mammals, proper storage and distribution of lipids in and between tissues is essential for the maintenance of energy homeostasis. In contrast, aberrantly high levels of triglycerides in the blood ("hypertriglyceridemia") represent a hallmark of the metabolic syndrome and type 2 diabetes. As hypertriglyceridemia has been identified as an important risk factor for cardiovascular complications, in this study we aimed to identify molecular mechanisms in aberrant triglyceride elevation under these conditions. RESEARCH DESIGN AND METHODS-To determine the importance of hepatic lipid handling for systemic dyslipidemia, we profiled the expression patterns of various hepatic lipid transporters and receptors under healthy and type 2 diabetic conditions. A differentially expressed lipoprotein receptor was functionally characterized by generating acute, liver-specific loss-and gain-of-function animal models. RESULTS-Weshow that the hepatic expression of lipid transporter lipolysis-stimulated lipoprotein receptor (LSR) is specifically impaired in mouse models of obesity and type 2 diabetes and can be restored by leptin replacement. Experimental imitation of this pathophysiological situation by liver-specific knockdown of LSR promotes hypertriglyceridemia and elevated apolipoprotein (Apo)B and E serum levels in lean wild-type and ApoE knockout mice. In contrast, genetic restoration of LSR expression in obese animals to wild-type levels improves serum triglyceride levels and serum profiles in these mice. CONCLUSIONS-The dysregulation of hepatic LSR under obese and diabetic conditions may provide a molecular rationale for systemic dyslipidemia in type 2 diabetes and the metabolic syndrome and represent a novel target for alternative treatment strategies in these patients. Diabetes 58:1040-1049, 2009 A ccording to recent estimates, obesity-related type 2 diabetes will be diagnosed in 200 -300 million people worldwide in 2010 (1). As part of the so-called metabolic syndrome, chronic hyperglycemia and dyslipidemia represent major causes for vascular complications in type 2 diabetic patients and result from defects in endocrine control systems that under normal conditions strictly balance glucose and lipid homeostasis within narrow limits (2).Dyslipidemia, as associated with diabetic metabolism and the metabolic syndrome, is characterized by a socalled proatherogenic blood lipid profile, comprising low levels of HDLs, increased LDLs, and strongly increased levels of serum triglycerides associated with VLDLs. Indeed, hepatic VLDL release is increased in diabetes and is thought to drive other aspects of the dyslipidemia associated with this disorder (3). In fact, hypertriglyceridemia is considered to represent an important risk factor for atherosclerosis and subsequent cardiovascular complications in type 2 diabetic patients (4).The regulation of plasma triglyceride levels is conferred through a complex interplay between different tissues and cell types (5). Dietary triglycerides within chylomicrons are hydrolyzed by adip...

Disialylated apolipoprotein C-III proteoform is associated with improved lipids in prediabetes and type 2 diabetes

“…LSR heterozygous mice display increased postprandial triglyceride levels, decreased clearance of lipid particles, and increased levels of proatherogenic lipoproteins following a Western diet (35). Silencing of hepatic LSR in mice has also been shown to lead to hypertriglyceridemia (43). We observed an increase in DiI-VLDL uptake in HepG2 cells in the presence of oleic acid that was inhibited by apoC-III.…”

Triglyceride-Rich Lipoproteins and Plasma Lipid Transport

“…Recent reports from 2 laboratories suggest that the "lipolysis-stimulated receptor" discovered in Bernard Bihain's laboratory 114 has a role in the endocytosis of remnants of VLDL as well as chylomicrons postprandially. 115,116 The lipolysis-stimulated receptor also Figure 4. This two-part diagram, modified from a publication in this journal, 112 depicts two aspects of the uptake and processing of chylomicron and large VLDL-remnants in hepatocytes.…”

Structure and Function of the Lipolysis Stimulated Lipoprotein Receptor

“…This provided clear in vivo evidence for the physiological role of LSR in lipoprotein clearance during the postprandial phase, as well as a potential link provided by this receptor that could explain mixed hyperlipidemia (hypercholesterolemia and hypertriglyceridemia), weight gain and atherosclerosis. A recent study confirmed this in which adenovirus-mediated expression of siRNA specifically targeting hepatic LSR led to a significant increase in postprandial triglyceridemia, accompanied by increased levels of both apoB and apoE (Narvekar et al, 2009). …”

“…LDL could therefore be internalized by LSR during the postprandial phase, but only if concentrations are sufficiently high to be able to compete with the higher affinity TG-rich lipoproteins for binding to LSR ( Figure 4). Indeed, this hypothesis is supported by the increase in LDL and plasma cholesterol observed in LSR +/-mice on a high-fat cholesterol-containing diet (Yen et al, 2008b), as well as the increased plasma cholesterol following specific hepatic LSR knockout (Narvekar et al, 2009). …”

“…The role of leptin in the regulation of LSR as well as the change in distribution of tissue lipids led towards the hypothesis that LSR could provide a molecular link between hyperlipidemia and obesity. Indeed, it was found that LSR expression was significantly diminished in obese mouse models, including the ob/ob, db/db and diet-induced obese (DIO) mouse (Narvekar et al, 2009;Yen et al, 2008a). If leptin either by its absence (ob/ob) or due to a leptin resistance (db/db or DIO) is unable to increase LSR levels during the postprandial phase, this could lead to suboptimal levels of this receptor.…”