Public release date: 5-Jun-2008
Contact: Nick Zagorski
nzagorski@asbmb.org
301-634-7366
American Society for Biochemistry and Molecular Biology
Niacin's role in maintaining good cholesterol
Appearing in the June issue of JLR
A research team has uncovered the likely target of niacin (vitamin B3) in the liver, which should provide a clearer picture of how this vitamin helps maintain adequate HDL-cholesterol levels in the blood and thus lower the risk of heart disease.
While niacin can increase plasma HDL levels, the mechanism of how it works has been mysterious, although it's believed that niacin does not actually increase HDL production. Recent work had uncovered that a component of ATP synthase (the protein that makes ATP) is present on the surface of liver cells, and this subunit known as the 'beta chain' can take up HDL.
Now, Moti Kashyap and colleagues found that this beta chain is the basis of niacin's effect. They added niacin to samples of human liver cells and found that treatment reduced the presence of Beta chain on the cell surface by ~27%, and as a result HDL uptake was reduced by ~35%. In comparison, nicotinamide, a related molecule with no clinical benefit, had far weaker effects.
These results indicate niacin hinders the liver from removing HDL from the blood, thus maintaining high plasma HDL levels. Importantly, niacin does not affect another major pathway known as "Reverse Cholesterol Transport." Therefore, it maintains HDL levels while still allowing the removal of other cholesterol types, explaining why niacin is especially beneficial.
The work also identifies a new drug target, as no other drug in currently known to raise HDL by inhibiting the surface expression of the beta chain of ATP synthase.
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From the article: "Niacin inhibits surface expression of ATP synthase B-chain in HepG2 cells: implications for raising HDL."
Article link: jlr.org
Corresponding Author: Moti L. Kashyap, Atherosclerosis Research Center, Veterans Administration Healthcare System, Long Beach, CA; Tel: 562-826-5844, email: Moti.Kashyap@va.gov
+++++++++++++++++Abstract++++++++++++++++++++
Journal of Lipid Research, Vol. 49, 1195-1201, June 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology
Niacin inhibits surface expression of ATP synthase ß chain in HepG2 cells: implications for raising HDL
Lin-Hua Zhang1, Vaijinath S. Kamanna, Michael C. Zhang and Moti L. Kashyap1
Atherosclerosis Research Center, Veterans Administration Healthcare System, Long Beach, CA; and Department of Medicine, University of California, Irvine, CA
This study was supported by grants from the Southern California Institute for Research and Education.
Published, JLR Papers in Press, March 3, 2008.
1 To whom correspondence should be addressed. e-mail: Linhua.zhang@va.gov (L-H.Z.); Moti.Kashyap@va.gov (M.L.K.)
Niacin is an effective agent for raising HDL, but its cellular target sites are largely unknown. We examined effects of niacin on the surface expression of ATP synthase ß chain, a newly described HDL/apolipoprotein A-I (apoA-I) receptor for HDL endocytosis, in HepG2 cells. A significant amount of immunodetectable ß chain was observed on the surface of HepG2 cells, which was competitively displaced by apoA-I. Niacin treatment reduced the surface expression of ß chain in HepG2 cells by ~27%, and decreased 125I-labeled HDL uptake up to ~35%. However, nicotinamide, a niacin metabolite that does not have clinical lipid effects, exhibited weaker inhibition on the ß chain cell surface expression, and failed to show inhibitory action on 125I-labeled HDL uptake. Furthermore, anti-ß chain antibody significantly reduced 125I-labeled HDL uptake and abolished the inhibitory effect of niacin. Niacin did not change ß chain mRNA expression. These data suggest that niacin inhibits cell surface expression of the ATP synthase ß chain, leading to reduced hepatic removal of HDL protein, thus implicating a potential cellular target for niacin action to raise HDL.
Supplementary key words hepatocytes • HDL receptor • nicotinic acid • flow cytometry |
