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Probing the Role of Hepatic Cholesterol Esterification in Atherosclerosis Promotion Via Liver‐Specific Depletion of ACAT2
Author(s) -
Brown Jonathan Mark,
Lemonidis Kristina M.,
Graham Mark J.,
Crooke Rosanne M.,
Rudel Lawrence L.
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a109-c
Subject(s) - cholesterol , chemistry , medicine , very low density lipoprotein , endocrinology , reverse cholesterol transport , apolipoprotein b , triglyceride , in vivo , bile acid , cholesteryl ester , phospholipid , lipoprotein , biochemistry , biology , microbiology and biotechnology , membrane
Due to its ability to esterify cholesterol in hepatocytes and enterocytes, ACAT2 is believed to promote atherosclerosis by driving both cholesterol absorption in the intestine and promoting packaging of cholesterol into VLDL in the liver. The purpose of these studies was to determine how liver‐specific depletion of ACAT2 via in vivo antisense oligonucleotide (ASO)‐mediated inhibition alters hepatic cholesterol and lipoprotein metabolism in a hyperlipidemic mouse model. Liver‐specific depletion (>85%) of ACAT2 resulted in a dramatic reduction in the packaging of cholesterol into apoB‐containing lipoproteins (VLDL, IDL, and LDL), while HDL cholesterol levels were not affected. In the liver of ACAT2‐ASO treated mice, total (TC), esterified (CE), free (FC) cholesterol and triglyceride (TG) concentrations all were decreased when compared to control mice. Furthermore, cholesterol, phospholipid, and bile acid concentrations in gall bladder bile were not altered in ACAT2‐ASO treated mice. Interestingly, during isolated liver perfusion, ACAT2‐ASO treated livers had augmented perfusate accumulation rates of FC and phospholipid (PL). Collectively, these studies provide the first insight into the hepatic itinerary of cholesterol, when cholesterol esterification is specifically inhibited within the liver.