Sr-Bi deficiency uncouples the development of hypertriglyceridemia and atherosclerosis from hepatic steatosis aand glucose intolerance in obese mice

Abstract

Scavenger receptor BI (SR-BI) plays a quantitative role in triglyceride

metabolism. However, the relevance of SR-BI in pa- thologies associated with disturbances

in triglyceride homeostasis, i.e. obesity and fatty liver disease, remains largely

unknown. We therefore investigated the metabolic phenotype of SR-BI knockout mice and wild- type controls after a high-fat diet challenge. Mice were fed a high-fat diet for 12 weeks. SR-BI knockout mice gained significantly more weight than wild- type control mice after 12 weeks of high-fat diet feeding (13±1 grams versus 9±1 grams, respectively; P<0.05). SR-BI deficiency was associated with higher plasma levels of free cholesterol (+111%; P<0.001) and cho- lesteryl esters (+89%; P<0.001) as well as hypertriglyceridemia (+40%; P<0.01). In contrast, liver triglyceride levels were lower (-29%; P<0.05) in SR-BI knockout mice, despite relatively high hepatic expression levels of lipogenic genes ACC (+54%; P<0.05) and SCD1 (+199%; P<0.01). Fasting blood glucose levels were higher in SR-BI knockout mice as compared to wild-type controls (+20%; P<0.01). However, SR-BI knockout mice could handle an oral bolus of glucose much better than wild-type mice as judged from the 45% lower (P<0.05) area under the curve of the oral glucose tolerance test. Notably, atherosclerotic lesions could be detected in the aortic root of all SR-BI knockout mice, while none were present in wild- type mice after the high-fat diet challenge. SR-BI deficiency disassociates hypertriglyceridemia, obesity, and atherosclerosis development from hepatic steatosis and glucose intolerance in high-fat diet-fed mice. Our studies provide additional proof for the biological relevance of SR-BI in total body triglyceride metabolism.