Abstract
Intestinal cholesterol absorption involves chylomicron and high density lipoprotein (HDL) pathways. Microsomal triglyceride transfer protein (MTP) and ATP binding cassette family A protein 1 (ABCA1) are critical for cholesterol transport by these pathways, respectively. Additionally, acyl Co-A:cholesterol acyltransferase 2 (ACAT2) plays an important role in cholesterol absorption. Intestinal MTP ablation significantly increased intestinal triglyceride and cholesterol levels and reduced their acute absorption. In contrast, ACAT2 deficiency had no effect on triglyceride absorption but significantly reduced cholesterol absorption. Individual deficiencies of ACAT2 and MTP reduced cholesterol absorption with chylomicrons. We hypothesized that their combined deficiency would increase cholesterol secretion with HDL; unexpectedly, their deficiency reduced secretion with both chylomicrons and HDL. Further, we observed significant reductions in intestinal ABCA1 expression in combined deficient mice. Thus, free cholesterol is unavailable for secretion by the HDL pathway in these mice. We speculate that reductions in ABCA1 expression and HDL secretion might be secondary to massive triglyceride accumulation associated with intestinal MTP deficiency.
Besides its role in cholesterol absorption, ACAT2 deficiency causes mild hypertriglyceridemia and reduces steatosis in mice fed high cholesterol diets by increasing hepatic lipoprotein production by unknown mechanisms. We show that this phenotype is preserved in the absence of intestinal MTP in ACAT2 deficient mice fed a Western diet. Further, we observed increases in hepatic MTP activity in these mice. Thus, ACAT2 deficiency might increase MTP expression to avoid steatosis. Therefore, ACAT2 inhibition might avert steatosis associated with high cholesterol diets by increasing MTP expression.