In Vivo Evidence for a Role of Adipose Tissue SR-BI in the Nutritional and Hormonal Regulation of Adiposity and Cholesterol Homeostasis

Abstract

Objectives-This study examines the role of insulin and angiotensin II in high-density lipoprotein (HDL) metabolism by focusing on the regulation and function of scavenger receptor type-BI (SR-BI) in adipose tissue. Methods and Results-Insulin or angiotensin II injection in wild-type mice induced a decrease in circulating HDL and it was associated with the translocation of SR-BI from intracellular sites to the plasma membrane of adipose tissue. Refeeding upregulated adipose HDL selective cholesteryl esters uptake and SR-BI proteins through transcriptional and posttranscriptional mechanisms. This occurred along with a decrease in serum HDL and an increase in adipose cholesterol content. Similar results were obtained with transgenic mice overexpressing locally angiotensinogen in adipose tissue. In adipose 3T3-L1 cell line, HDL induced lipogenesis by increasing liver X receptor binding activity. This mechanism was dependent of insulin and angiotensin II. Key Words: adipose tissue Ⅲ angiotensin II Ⅲ high-density lipoprotein Ⅲ insulin A dipose tissue has a central role in the energy metabolism adaptation to the nutritional environment because of its ability to store energy as triglycerides. Besides its role in triglyceride storage, adipose tissue is also the body's largest pool of cholesterol store, representing Ϸ25% of whole-body cholesterol in human. 1 A particular interest of adipocytes is that these cells accumulate cholesterol proportionally to triglycerides. Because of an extremely low cholesterol de novo synthesis, 2 adipocytes must acquire cholesterol from exogenous sources. Interestingly, clinical observations have found a correlation between obesity and low levels of high-density lipoprotein (HDL) cholesterol, 3 which is the reflect of an increased incidence of atherosclerosis. 4 There is also growing evidence that altered insulin sensitivity or increased angiotensin II concentrations, which occur along with obesity, play a crucial role in the acceleration of atherosclerosis but mechanisms are not yet fully deciphered. 5,6 The scavenger receptor type-BI (SR-BI) has been identified as a membrane transporter involved in the selective cholesteryl esters (CEs) uptake from HDL. 7 The pivotal role of SR-BI in lipoprotein metabolism and cholesterol transport in steroidogenic tissues and liver has been well-established. 8 SR-BI is also expressed in adipocytes, but little is known about its function and regulation in these cells. 9 Recently, studies from our laboratory have reported that SR-BI provide an important source of cholesterol from HDL in adipose cell lines and that insulin and angiotensin II induce the translocation of this receptor leading to an increase in cholesterol influx and storage. 10,11 However, the nutritional and hormonal regulation of this translocation and its potential consequences on plasma HDL have not been yet explored in vivo. Conclusions-OurBecause cholesterol plays a role in the regulation of signal transduction and gene expression, we further investigated the consequence of the cho...

Local adipose tissue renin-angiotensin system

“…A recent study demonstrated that injecting Ang II into wild-type mice reduced circulating highdensity lipoprotein (HDL), which was associated with the translocation of scavenger receptor type B1 (SR-B1) proteins to the plasma membrane in adipose tissue [28]. Similar results were obtained in transgenic mice overexpressing angiotensinogen in adipose tissue, raising the possibility that elevations in adipocyte-derived Ang II may contribute to dyslipidemias of obesity through regulation of adipocyte SR-BI and HDL clearance.…”

Antipsychotics-induced metabolic alterations: Focus on adipose tissue and molecular mechanisms

“…However, adipose tissue is a major pool of free cholesterol (Krause and Hartman, 1984;Prattes et al, 2000) and some studies suggest an underappreciated role of adipose tissue in cholesterol metabolism (Verghese et al, 2007;Yvan-Charvet et al, 2007). Exposure of rats to clozapine and/or olanzapine increased the accumulation of cholesterol in liver (Ferno et al, 2009) and adipose tissue (Jassim et al, 2012).…”

Adipose Modulation of ABCG1 Uncovers an Intimate Link Between Sphingomyelin and Triglyceride Storage

“…Consistent with the view that adipose tissue behaves as a cholesterol sink, and its accumulation is proportional to triglycerides in response to nutritional changes to maintain cellular integrity and to regulate cellular hypertrophy, it is not surprising that adipocytes have developed a unique ability to deal with cholesterol (1). It may be for this reason that adipocytes have evolved with an extremely limited capacity to perform de novo cholesterol synthesis (1) but possess multiple strategies to extract cholesterol from circulating lipoproteins (5,6). Despite cholesterol being delivered as cholesteryl ester in adipocytes, approximately 95% of cholesterol paradoxically exists as free cholesterol (FC) (7) and resides in the plasma membrane or the cytosolic interface of lipid droplets where it is readily available for mobilization (8).…”

“…This contrasts to scavenger receptor class B type I (SR-BI), which is not an LXR target and facilitates the bidirectional flux of cholesterol depending on the cholesterol status of the cells (11). Remarkably, HDL cholesterol transport machinery is highly represented in adipocytes (5,6,13) but the relevance to obesity and metabolic complications remains poorly understood. While LXR-deficient mice are leaner than littermate controls and are protected against diet-induced obesity, the mechanisms that control fat loss in these mice are still a matter of debate and could involve either reduced lipogenesis, enhanced lipid oxidation and lipolysis, or reduced cholesterol efflux pathways (14).…”

“…Consistent with apoE being an LXR target gene in adipocyte (13), apoE-deficient mice also exhibit a lean phenotype and are resistant to dietinduced obesity (15)(16)(17). However, the interpretation of this phenotype can be confounded by the fact that apoE plays a dual role promoting cholesterol efflux and mediating lipoprotein clearance (15-17) similar to SR-BI (5,6,11). LXRs also transcriptionally regulate the cholesterol efflux transporters ABCA1 and ABCG1, and deficiency of ABCA1 is associated with decreased body weight (18), while ABCG1 deficiency protects against diet-induced obesity (19).…”