Mechanism for Endogenously Expressed ApoE Modulation of Adipocyte Very Low Density Lipoprotein Metabolism

Abstract

Triglyceride-rich lipoproteins distribute energy in the form of fatty acids to peripheral tissues. We have previously shown that the absence of endogenous adipocyte apoE expression impairs adipocyte triglyceride acquisition from apoE-containing triglyceride-rich lipoproteins in vitro and in vivo. Studies were performed to evaluate the mechanism(s) for this impairment. We excluded a role for secreted apoE in accounting for the difference in very low density lipoprotein (VLDL)-induced adipocyte triglyceride accumulation using cross-incubation studies to show that secreted apoE did not enhance triglyceride synthesis in apoE knockout (EKO) adipocytes incubated with apoE-containing VLDL. Subsequent experiments established that both endocytic and lipase-mediated pathways for lipid acquisition from VLDL were impaired in EKO adipocytes. Binding and internalization of VLDL to EKO adipocytes were significantly lower due to decreased expression or redistribution of low density lipoprotein receptor family proteins. An important role for the VLDL receptor for contributing to differences in VLDL binding between wild-type and EKO adipocytes was identified. Lipoprotein lipase-dependent adipocyte lipogenesis was also significantly decreased in EKO adipocytes even though they secreted as much or more lipolytic activity. This decrease was related to impaired fatty acid internalization in EKO cells. Evaluation of potential mechanisms revealed reduced caveolin-1 and plasma membrane raft expression in EKO adipocytes. Increasing caveolin expression in EKO adipocytes increased fatty acid internalization. Our results establish a role for endogenous adipocyte apoE in VLDL-induced adipocyte lipogenesis by impacting both endocytic and lipoprotein lipase-mediated metabolic pathways. Reduced adipocyte apoE expression, for example that accompanying obesity, will suppress adipocyte acquisition of lipid from apoE-containing VLDL.

Very Low Density Lipoprotein Receptor (VLDLR) Expression Is a Determinant Factor in Adipose Tissue Inflammation and Adipocyte-Macrophage Interaction

“…Moreover, apoE in VLDL increases VLDL uptake (38) and adipocyte hypertrophy (40). Similarly, suppression of apoE expression in adipocyte is associated with a reduction of adipocyte size and decline of VLDLR expression, suggesting a link between reduced VLDL uptake and VLDLR expression (41,42). The expressions of apoE as well as that of LDLR-related protein and LDLR, receptors that could bind VLDL, were not altered by VLDLR deficiency (results not shown).…”

Association between Apolipoprotein E Variants and Obesity-Related Traits in Mexican School Children

“…The structural variation in the ApoE gene has been widely studied in the context of cardiovascular risk, particularly in lipoprotein metabolism [8,9,10,11,12]. The role of ApoE in adipose tissue, and its relation with obesity, has recently been investigated in animal models [16,17,18] and seems to be independent of the blood lipid transport process.…”

“…The ApoE influence on adiposity traits might be explained by the endogenous ApoE modulation on the triglyceride content of adipocytes, independently of exogenous ApoE [16,17] and the counteracted ApoE ability to promote the removal of atherogenic lipoproteins from the circulation and the formation of ApoE-containing HDL particles when excess dietary lipids are present in the circulation. This excess promotes the enhanced deposition of dietary lipids to adipose tissue [15].…”

“…ApoE is also involved in lipid influx into cells, including adipocytes. ApoE is highly expressed in adipose tissue and is involved in the cell lipid influx, and studies conducted in animal models have demonstrated the contribution of ApoE to the size and triglyceride content in adipocytes [15,16,17]. A study in five different species demonstrated that ApoE expression may vary across adipose tissue depots.…”

Genetically Modified Animal Models for Lipoprotein Research

“…Furthermore, a recent study suggests that the expression of VLDLRs is affected by PCSK9 (Roubtsova, 2011). Surprisingly, adipose tissues of apoE-KO mice did not express LDLR, VLDLR, and LDLR-related proteins (Huang, 2009), although wild-type mice developed these receptors in adipose tissue. Since the VLDLR has various functions, genetically modified animals may contribute to further studies.…”