VLDL Induces Adipocyte Differentiation in ApoE-Dependent Manner

Abstract

Objective-To clarify the role of very low density lipoprotein (VLDL) and apolipoprotein E (apoE) in adipogenesis, we studied newly developed hyperlipidemic obese (ob/ob;apoE Ϫ/Ϫ ) mice. Because hydrolysis of VLDL is believed to be the major source of adipogenic free fatty acids, a higher plasma level of VLDL in these mice should exaggerate obesity. Methods and Results-When fed a high-fat, high-cholesterol diet, ob/ob;apoE Ϫ/Ϫ mice did not show increased body weight or an increased amount of adipose tissue in spite of increased plasma VLDL levels, whereas ob/ob mice showed an increased body weight and amount of adipose tissue, suggesting that there is a novel apoE-dependent pathway for adipogenesis. In vitro experiments using bone marrow stromal cells and 3T3-L1 cells confirmed this notion. ApoE-deficient VLDL did not induce adipogenesis, whereas normal VLDL induced adipogenesis in these cells. The incubation of apoE-deficient VLDL with recombinant human apoE restored its adipogenic activity. Tetrahydrolipstatin, a lipoprotein lipase inhibitor, did not affect the adipogenic activity of VLDL, suggesting that hydrolysis of VLDL did not play a major role in its effects. In fact, lipid components of VLDL or free fatty acids induced only partial adipogenesis. Key Words: VLDL Ⅲ apolipoprotein E Ⅲ lipoprotein lipase Ⅲ obesity Ⅲ adipogenesis F ree fatty acids (FFAs) generated by the hydrolysis of VLDL by lipoprotein lipase (LPL) have been believed to the major driving force in adipogenesis and the development of obesity. FFAs can regulate various steps of adipogenesis, including the activation of early signals, such as peroxisome proliferator-activated receptor-␥ (PPAR␥), induction of adipocyte-specific genes, and maturation to heterogeneous adipocytes containing different sizes of lipid droplets or metabolic activities. 1,2 LPL, secreted from adipocytes and other cell types, is the rate-limiting enzyme for this process. 3,4 Heparan sulfate proteoglycan, the VLDL receptor, and LDL receptor-related protein (LRP) act as cell surface anchors for LPL. [5][6][7] Deficiency of this enzyme induces severe hypertriglyceridemia in humans and mice. 8,9 Homozygous knockout mice are lipodystrophic and die of hypertriglyceridemia soon after birth. 8 However, the importance of LPL in adipogenesis has been challenged by recent investigations studying various new mouse models and humans. Adipose tissue-specific knockout of LPL resulted in normal adiposity, which was mainly due to increased de novo lipogenesis in adipocytes. 10 Crebbp heterozygous mice show lipodystrophy with a change in the expression of a series of genes related to lipid metabolism, suggesting that adipogenesis is a complex process regulated by different steps. 11 Rodents deficient in leptin or leptin receptors show both obesity and increased activity of fatty acid synthase, suggesting the importance of intrinsic lipogenesis in obesity. 12 Human LPL deficiency and apoC-II deficiency result in impaired hydrolysis of VLDL and chylomicron but are usually associated with no...

Involvement of Apolipoprotein E in Excess Fat Accumulation and Insulin Resistance

“…Insulin sensitivity was markedly greater in apoE Ϫ/Ϫ ;Ay/ϩ than in apoE ϩ/ϩ ;Ay/ϩ mice. Recently, several attempts to induce obesity in apoE Ϫ/Ϫ mice have been reported, but the results have been somewhat controversial (12)(13)(14). In the present study, in addition to inhibition of adiposity and insulin resistance with apoE deficiency, adenoviral apoE replenishment reversed inhibition of obesity and glucose intolerance.…”

“…We have recently reported that alterations in metabolism in adipose tissue affect food intake amounts (19). However, ob/ob;apoE Ϫ/Ϫ mice are also reportedly resistant to obesity (14). Since ob/ob mice are leptin deficient, the obesity resistance in ob/ob;apoE Ϫ/Ϫ mice is not mediated by leptin signaling, e.g., leptin sensitization, although food intake and energy expenditure were not measured in the earlier study (14).…”

“…These findings directly demonstrate apoE involvement in the development of obesity and obesity-related disorders of glucose metabolism and insulin sensitivity. Chiba et al (14) previously reported that ob/ob;apoE Ϫ/Ϫ mice are also resistant to obesity. They attributed decreased adiposity in ob/ob;apoE Ϫ/Ϫ mice to impaired adipocyte differentiation based on in vitro findings that expression levels of aP2 and peroxisome proliferator-activated receptor-␥ were markedly lower when bone marrow stromal cells and 3T3-L1 cells were cultured with apoE-less VLDL.…”

“…High-fat chow induces obesity in apoE Ϫ/Ϫ mice in a manner similar to that in wild-type C57BL/6 mice, while apoE deficiency produced resistance to some obesity-related phenotypic features, including hyperinsulinemia and hyperglycemia (13). On the other hand, Chiba et al reported that apoE deficiency in ob/ob mice resulted in neither increased body weight nor adiposity, but glucose metabolism and insulin sensitivity were not examined (14). They attributed decreased adiposity in ob/ob;apoE Ϫ/Ϫ mice to impaired adipocyte differentiation based on in vitro findings obtained using bone marrow stromal cells and 3T3-L1 cells.…”

Hepatocyte Growth Factor Fusion Protein Having Collagen-Binding Activity (CBD-HGF) Accelerates Re-endothelialization and Intimal Hyperplasia in Balloon-injured Rat Carotid Artery

“…Real-time PCR was carried out using the Light Cycler (Roche Diagnostic GmbH, Mannheim, Germany) and the SYBR green PCR kit (Qiagen Inc., CA, USA), as described previously 19) . The gene-specific oligonucleotide sequences were as follows.…”