Adipocyte Modulation of High-Density Lipoprotein Cholesterol

Abstract

Background-Adipose harbors a large depot of free cholesterol. However, a role for adipose in cholesterol lipidation of high-density lipoprotein (HDL) in vivo is not established. We present the first evidence that adipocytes support transfer of cholesterol to HDL in vivo as well as in vitro and implicate ATP-binding cassette subfamily A member 1 (ABCA1) and scavenger receptor class B type I (SR-BI), but not ATP-binding cassette subfamily G member 1 (ABCG1), cholesterol transporters in this process. Methods and Results-Cholesterol efflux from wild-type, ABCA1Ϫ/Ϫ , SR-BI Ϫ/Ϫ, and ABCG1 Ϫ/Ϫ adipocytes to apolipoprotein A-I (apoA-I) and HDL3 were measured in vitro. 3T3L1 adipocytes, labeled with 3 H-cholesterol, were injected intraperitoneally into wild-type, apoA-I transgenic, and apoA-I Ϫ/Ϫ mice, and tracer movement onto plasma HDL was monitored. Identical studies were performed with labeled wild-type, ABCA1 Ϫ/Ϫ , or SR-BI Ϫ/Ϫ mouse embryonic fibroblast adipocytes. The effect of tumor necrosis factor-␣ on transporter expression and cholesterol efflux was monitored during adipocyte differentiation. Cholesterol efflux to apoA-I and HDL3 was impaired in ABCA1 Ϫ/Ϫ and SR-BI Ϫ/Ϫ adipocytes, respectively, with no effect observed in ABCG1 Ϫ/Ϫ adipocytes. Intraperitoneal injection of labeled 3T3L1 adipocytes resulted in increased HDL-associated 3 H-cholesterol in apoA-I transgenic mice but reduced levels in apoA-I Ϫ/Ϫ animals. Intraperitoneal injection of labeled ABCA1 Ϫ/Ϫ or SR-BI Ϫ/Ϫ adipocytes reduced plasma counts relative to their respective controls. Tumor necrosis factor-␣ reduced both ABCA1 and SR-BI expression and impaired cholesterol efflux from partially differentiated adipocytes. Conclusions-These data suggest a novel metabolic function of adipocytes in promoting cholesterol transfer to HDL in vivo and implicate adipocyte SR-BI and ABCA1, but not ABCG1, in this process. Furthermore, adipocyte modulation of HDL may be impaired in adipose inflammatory disease states such as type 2 diabetes mellitus. Clinical Perspective on p 1355Lipidation of HDL is determined via a number of cholesterol transporters in several cholesterol-rich tissues. Although macrophage cholesterol efflux to HDL plays a major role in attenuating atherosclerosis, macrophages play a minor role in regulation of HDL-C levels. 4 In contrast, hepatic ATPbinding cassette subfamily A member 1 (ABCA1), through lipidation of apolipoprotein A-I (apoA-I), is required for formation of nascent HDL particles. 5 Indeed, in cholesterolrich tissues, both hepatic and extrahepatic, ABCA1 has discrete and essential roles in the maintenance of plasma HDL-C. 6,7 ATP-binding cassette subfamily G member 1 (ABCG1) mediates cholesterol efflux from macrophages to mature HDL particles 8,9 and may play a role in regulating plasma HDL-C levels. 10 In contrast to ABC transporters, scavenger receptor class B type I (SR-BI) is a bidirectional transporter that plays a major role in hepatic uptake of HDL Received July 25, 2009; accepted January 15, 2010. 15,16 In fact, adip...

Adiponectin and the mediation of HDL-cholesterol change with improved lifestyle: the Look AHEAD Study

“…Although these processes may infl uence HDL-C levels, our data and the experimental evidence for an ADN effect on apoA-I and ATP-binding cassette transporter expression ( 4,22,23 ) support a direct, triglyceride-independent effect of ADN on HDL-C. Recently, it has been reported that the upstream effects of ADN are mediated by activation of ceramidase and its effects on the formation of sphingosine-1-phosphate (S1P) ( 29 ).…”

“…In these animals, there are decreases in apoA-I levels and in the expression of ATP-binding cassette transporters in liver, suggesting that ADN defi ciency may impair HDL assembly. Recent reports have also identifi ed the presence of ATP-binding cassette transporters in adipocytes and have confi rmed an active role for adipose tissue in the synthesis of HDL ( 4,23 ). However, differences in HDL metabolism between rodents and humans ( 24 ) and in the posttranslational modifi cations of ADN, which have functional implications and vary by species ( 25 ), preclude the extrapolation of ADN and HDL-C mouse fi ndings to humans.…”

Regulation of signal transduction by HDL

“…SR-BI is required for HDL modulation of endothelial cell phenotype ( 56,60,64 ) and for the actions of HDL in EPC ( 57 ). SR-BI also mediates the actions of apoA-I and/or HDL in neutrophils ( 25 ), adipocytes ( 111 ), and pancreatic ␤ cells ( 36 ).…”

HDL abnormalities in nephrotic syndrome and chronic kidney disease

“…Heavy uptake of glucose from the peritoneal dialy sis fluid can also lead to a rise in plasma triglyceride levels 3 . Other factors that modify the serum lipid profile in this population include systemic inflammation, malnutrition, use of lipid-altering drugs (such as statins and fibrates), and exposure to sevelamer -a phosphate binding resin that markedly lowers serum cholesterol levels by binding and sequestering bile acids in the intestinal tract 7,8 . Furthermore, use of steroids and certain immunosuppressive medications, such as rapamycin and calcineurin inhibitors, that are frequently administered to renal transplant recipients can also affect lipid metabolism and serum lipid profile 3 .…”