title: Intestine-specific MTP and global ACAT2 deficiency lowers acute cholesterol absorption with chylomicrons and HDLs.
abstract: 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.
authors.affiliation: Departments of Cell Biology and Pediatrics, SUNY Downstate Medical Center, Brooklyn, NY 11203 Veterans Affairs New York Harbor Healthcare System, Brooklyn, NY 11209.
authors.forename: Jahangir
authors.initials: J
authors.lastname: Iqbal
authors.affiliation: Departments of Cell Biology and Pediatrics, SUNY Downstate Medical Center, Brooklyn, NY 11203 Veterans Affairs New York Harbor Healthcare System, Brooklyn, NY 11209.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Boutjdir
authors.affiliation: Departments of Pathology and Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC 27104.
authors.forename: Lawrence L
authors.initials: LL
authors.lastname: Rudel
authors.affiliation: Departments of Cell Biology and Pediatrics, SUNY Downstate Medical Center, Brooklyn, NY 11203 Veterans Affairs New York Harbor Healthcare System, Brooklyn, NY 11209.
authors.forename: M Mahmood
authors.initials: MM
authors.lastname: Hussain
mesh_terms: D000101:Acetyl-CoA C-Acetyltransferase / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D002791:Cholesterol, Dietary / Q000378:metabolism; D002914:Chylomicrons / Q000378:metabolism*; D066273:Diet, Western / Q000009:adverse effects; D004041:Dietary Fats / Q000378:metabolism; D020895:Enterocytes / Q000378:metabolism; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism*; D008075:Lipoproteins, HDL / Q000097:blood / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D009928:Organ Specificity; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D002791:Cholesterol, Dietary; D002914:Chylomicrons; D004041:Dietary Fats; D008075:Lipoproteins, HDL; D012333:RNA, Messenger; C106092:microsomal triglyceride transfer protein; D002784:Cholesterol; D000101:Acetyl-CoA C-Acetyltransferase
keywords: acyl-CoA:cholesterol acyltransferase 2; chylomicrons; high density lipoproteins; microsomal triglyceride transfer protein