In addition to providing potential mechanisms to account for the effects of pioglitazone on liver FFA and TG metabolism, our results demonstrate that pioglitazone-induced plasma hypercholesterolemia in KKAy mice, or the higher levels of LDL-C/HDL-C observed in diabetic patients treated with pioglitazone, may at least in part be explained by decreased hepatic expression of LDL-R, SR-BI, and HL, resulting in impaired clearance of circulating cholesterol from the liver. Here, LDLR is linked to familial hypercholesterolemia.