Brown adipose tissue (BAT) burns fatty acids for heat production to defend the body against cold and has recently been shown to be present in humans. Triglyceride-rich lipoproteins (TRLs) transport lipids in the bloodstream, where the fatty acid moieties are liberated by the action of lipoprotein lipase (LPL). Peripheral organs such as muscle and adipose tissue take up the fatty acids, whereas the remaining cholesterol-rich remnant particles are cleared by the liver. Elevated plasma triglyceride concentrations and prolonged circulation of cholesterol-rich remnants, especially in diabetic dyslipidemia, are risk factors for cardiovascular disease. However, the precise biological role of BAT for TRL clearance remains unclear. Here we show that increased BAT activity induced by short-term cold exposure controls TRL metabolism in mice. Cold exposure drastically accelerated plasma clearance of triglycerides as a result of increased uptake into BAT, a process crucially dependent on local LPL activity and transmembrane receptor CD36. In pathophysiological settings, cold exposure corrected hyperlipidemia and improved deleterious effects of insulin resistance. In conclusion, BAT activity controls vascular lipoprotein homeostasis by inducing a metabolic program that boosts TRL turnover and channels lipids into BAT. Activation of BAT might be a therapeutic approach to reduce elevated triglyceride concentrations and combat obesity in humans.

Scavenger receptor BI (SR-BI) is known to mediate the selective uptake of high density lipoprotein (HDL) cholesteryl ester (CE) in liver and steroidogenic tissues. To evaluate the role of SR-BI in plasma lipoprotein metabolism, we have generated transgenic mice with liverspecific overexpression of murine SR-BI. On a chow diet SR-BI transgenic (SR-BI Tg) mice have decreased HDL-CE, apoA-I, and apoA-II levels; plasma triglycerides, low density lipoprotein (LDL) cholesterol, and very low density lipoprotein (VLDL) and LDL apoB were also decreased, compared with control mice. Turnover studies using non-degradable CE and protein labels showed markedly increased total and selective uptake of HDL-CE in the liver and increased HDL protein catabolism in both liver and kidney. To evaluate the changes in apoB further, mice were challenged with high fat, high cholesterol diets. In SR-BI Tg mice plasma apoB levels were only 3-15% of control levels, and the dietary increase in VLDL and LDL apoB was virtually abolished. These studies show that steady state overexpression of hepatic SR-BI reduces HDL levels and increases reverse cholesterol transport. They also indicate that SR-BI can play a role in the metabolism of apoB-containing lipoproteins. The dual effects of increased reverse cholesterol transport and lowering of apoB-containing lipoproteins that result from hepatic SR-BI overexpression could have anti-atherogenic consequences.The risk of coronary heart disease is inversely correlated with the levels of plasma high density lipoproteins (HDL) 1 (1, 2). HDL appears to transport cholesterol from peripheral tissues to the liver for catabolism and secretion (reverse cholesterol transport) (3, 4). A putative cell-surface receptor for this process has been identified (5). This receptor, scavenger receptor BI (SR-BI), mediates high affinity binding of HDL and the selective uptake of HDL cholesteryl ester (CE) (5), a process for delivery of cholesteryl ester into cells without degradation of HDL proteins (6). Furthermore, SR-BI mRNA and protein levels are highest in adrenal gland, ovary, testis, and liver, tissues that display greatest selective cholesteryl ester uptake from HDL (7-9). SR-BI expression in steroidogenic cells is regulated by hormones and mutations that alter cholesterol supply or metabolism in those tissues in vivo (8 -11). More recently, strong support for the role of SR-BI in HDL metabolism has been provided by studies of mice with a targeted mutation resulting in decreased SR-BI gene expression (12, 13). These mice demonstrate increased plasma HDL cholesterol, decreased adrenal cholesterol content (12, 13), and decreased hepatic fractional clearance rate (FCR) for HDL-CE (13), suggesting that SR-BI is the major molecule mediating HDL-CEselective uptake in the liver. By contrast, adenovirus-mediated, hepatic overexpression of SR-BI in mice results in depletion of plasma HDL and an increase in biliary cholesterol concentration (14). Although these studies nicely demonstrate the effect of acute overexpression of ...

Scavenger receptor BI (SR-BI) is a cell surface receptor that binds high density lipoproteins (HDL) and mediates selective uptake of HDL cholesteryl esters (CE) in transfected cells. To address the physiological role of SR-BI in HDL cholesterol homeostasis, mice were generated bearing an SR-BI promoter mutation that resulted in decreased expression of the receptor in homozygous mutant (designated SR-BI att) mice. Hepatic expression of the receptor was reduced by 53% with a corresponding increase in total plasma cholesterol levels of 50-70% in SR-BI att mice, attributable almost exclusively to elevated plasma HDL. In addition to increased HDL-CE, HDL phospholipids and apo A-1 levels were elevated, and there was an increase in HDL particle size in mutant mice. Metabolic studies using HDL bearing nondegradable radiolabels in both the protein and lipid components demonstrated that reducing hepatic SR-BI expression by half was associated with a decrease of 47% in selective uptake of CE by the liver, and a corresponding reduction of 53% in selective removal of HDL-CE from plasma. Taken together, these findings strongly support a pivotal role for hepatic SR-BI expression in regulating plasma HDL levels and indicate that SR-BI is the major molecule mediating selective CE uptake by the liver. The inverse correlation between plasma HDL levels and atherosclerosis further suggests that SR-BI may inf luence the development of coronary artery disease.It is well established that plasma concentrations of high density lipoprotein (HDL) cholesterol are inversely proportional to the risk of developing atherosclerosis and coronary artery disease (1). Although the protective mechanism is not known, HDL is thought to reduce plaque formation by removing cholesterol from arterial cells and delivering it to the liver as cholesteryl ester (CE) for bile acid synthesis and secretion, a process referred to as reverse cholesterol transport (2). HDL also delivers CE to steroidogenic tissues (adrenal gland, ovary, and testis), where it serves as substrate for steroid hormone synthesis (reviewed in ref.3). The uptake of HDL cholesterol by cells involves selective transfer of CE to the cell without uptake and degradation of HDL proteins, a process known as selective lipid uptake (4, 5). This is markedly different from the mechanism of clearance of low density lipoproteins (LDL), which involves receptor-mediated endocytosis and intracellular degradation of the entire lipoprotein particle (6).Whereas the receptor that mediates LDL clearance was identified well over a decade ago (6), a functional HDL receptor has only recently been identified. Acton et al. (7) demonstrated that scavenger receptor BI (SR-BI), a multiligand cell surface receptor isolated from Chinese hamster ovary cells by expression cloning (8), binds HDL with high affinity and mediates selective cholesterol uptake in transfected cells. Furthermore, the receptor is primarily expressed in those tissues exhibiting selective lipid uptake in vivo: liver, adrenal gland, ovary, ...