Intestine-specific MTP and global ACAT2 deficiency lowers acute cholesterol absorption with chylomicrons and HDLs.
Intestinal cholesterol absorption involves the chylomicron and HDL pathways and is dependent on microsomal triglyceride transfer protein (MTP) and ABCA1, respectively. Chylomicrons transport free and esterified cholesterol, whereas HDLs transport free cholesterol. ACAT2 esterifies cholesterol for secretion with chylomicrons. We hypothesized that free cholesterol accumulated during ACAT2 deficiency may be secreted with HDLs when chylomicron assembly is blocked. To test this, we studied cholesterol absorption in mice deficient in intestinal MTP, global ACAT2, and both intestinal MTP and global ACAT2. Intestinal MTP ablation significantly increased intestinal triglyceride and cholesterol levels and reduced their transport with chylomicrons. In contrast, global ACAT2 deficiency had no effect on triglyceride absorption but significantly reduced cholesterol absorption with chylomicrons and increased cellular free cholesterol. Their combined deficiency reduced cholesterol secretion with both chylomicrons and HDLs. Thus, contrary to our hypothesis, free cholesterol accumulated in the absence of MTP and ACAT2 is unavailable for secretion with HDLs. Global ACAT2 deficiency causes mild hypertriglyceridemia and reduces hepatosteatosis 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 global 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 hepatosteatosis in cholesterol-fed animals. Therefore, ACAT2 inhibition might avert hepatosteatosis associated with high cholesterol diets by increasing hepatic MTP expression and lipoprotein production.
['Iqbal|Jahangir|J|', 'Boutjdir|Mohamed|M|', 'Rudel|Lawrence L|LL|', 'Hussain|M Mahmood|MM|']
D000101:Acetyl-CoA C-Acetyltransferase D000818:Animals D002352:Carrier Proteins D002784:Cholesterol D002791:Cholesterol, Dietary D002914:Chylomicrons D066273:Diet, Western D004041:Dietary Fats D020895:Enterocytes D005786:Gene Expression Regulation D055786:Gene Knockout Techniques D007408:Intestinal Absorption D007413:Intestinal Mucosa D008075:Lipoproteins, HDL D008099:Liver D008297:Male D051379:Mice D009928:Organ Specificity D012333:RNA, Messenger
chylomicrons microsomal triglyceride transfer protein acyl-CoA:cholesterol acyltransferase 2 high density lipoproteins