title: Dietary cholate increases plasma levels of apolipoprotein B in mice by posttranscriptional mechanisms.
abstract: To induce atherogenesis in mice, a high fat (HF) diet is supplemented with cholic acid (CA), which increases apoB-containing particles and lower apoA-I-containing particles. HF diet without CA increases levels of both HDL and LDL, suggesting that CA may be responsible for the elevation of LDL and lowering of HDL. The mechanism of dietary CA-induced lowering of apoA-I-containing particles has recently been reported. In this study, we examined the mechanism of CA- and HF-induced elevation of apoB-containing lipoproteins in mice. Mice were fed the following four diets: control chow (C), high fat high cholesterol, (HF), control and 0.5% cholate (CA), and HF+CA. Dietary CA increased the plasma levels of apoB-containing particles by approximately 2-fold when compared to control; VLDL levels increased 2-fold, and LDL levels increased 1.3-fold. On HF diet, VLDL increased by 1.4-fold, and LDL by 2-fold, suggesting that CA and HF-induced increases of apoB-containing particles occurred by different mechanisms. We investigated the potential mechanisms regulating plasma levels of apoB in CA- and HF-fed mice. Although hepatic apoB mRNA levels did not change on CA diet, apoB-100 mRNA increased relative to B-48 as a result of decreased editing of apoB mRNA. Measurements of hepatic LDL receptor mRNA suggested that CA diet down-regulated LDL receptor mRNA, possibly by increasing the levels of hepatic cholesterol. Since plasma and hepatic vitamin E levels did not show significant changes on CA-containing diets, it suggests that dietary CA did not act by increasing the absorption of dietary fat. Hepatic lipase, known to modulate plasma levels of apoB-containing particles, did not show changes in CA- or HF-fed mice. Taken together, these results suggest that dietary CA increased apoB-containing particles both in chow-fed and fat-fed mice by enhancing the relative production of apoB-100, and also by reducing LDL receptor-mediated clearance of apoB-containing particles. Thus, dietary cholate modulates plasma levels of apoB primarily by posttranscriptional mechanisms.
authors.affiliation: Division of Atherosclerosis, Nutrition and Lipid Research, Department of Internal Medicine, Washington University, St. Louis, MO 63110, USA. ajits@esperion.com
authors.forename: R A
authors.initials: RA
authors.lastname: Srivastava
authors.forename: M
authors.initials: M
authors.lastname: Averna
authors.forename: N
authors.initials: N
authors.lastname: Srivastava
authors.forename: M E
authors.initials: ME
authors.lastname: Pape
mesh_terms: D000818:Animals; D001055:Apolipoproteins B / Q000097:blood* / Q000378:metabolism; D001057:Apolipoproteins E / Q000378:metabolism; D015152:Blotting, Northern; D020355:Cholates / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism; D019826:Cholic Acid / Q000737:chemistry* / Q000494:pharmacology; D004032:Diet; D015536:Down-Regulation; D008077:Lipoproteins, LDL / Q000378:metabolism; D008079:Lipoproteins, VLDL / Q000096:biosynthesis; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism; D012260:Ribonucleases / Q000378:metabolism; D014810:Vitamin E / Q000096:biosynthesis
chemical_list: D001055:Apolipoproteins B; D001057:Apolipoproteins E; D020355:Cholates; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D012333:RNA, Messenger; D011973:Receptors, LDL; D014810:Vitamin E; D002784:Cholesterol; D012260:Ribonucleases; D019826:Cholic Acid