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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:2948-2954.)
© 1997 American Heart Association, Inc.

Articles

Liver LDL Receptor mRNA Expression Is Decreased in Human ApoB/CETP Double Transgenic Mice and Is Regulated by Diet as Well as the Cytokine Oncostatin M

Jingwen Liu; Y. Lynda Zhang; Michael J. Spence; Robert E. Vestal; Philip M. Wallace; ; David S. Grass

From the Department of Veterans Affairs Medical Center and Mountain States Medical Research Institute, Boise, Idaho (J.L., Y.L.Z., M.J.S., R.E.V.); the Departments of Medicine and Pharmacology, University of Washington (R.E.V.), and Bristol-Myers Squibb Pharmaceutical Research Institute (P.M.W.), Seattle, Wash; and Chrysalis DNX Transgenic Sciences, Princeton, NJ (D.S.G.).

Correspondence to Jingwen Liu, PhD, Palo Alto VA Health Care System, 3801 Miranda Ave, Palo Alto, CA 94304. E-mail Liu{at}icon.Palo-Alto.med.VA.gov

Abstract We have investigated liver LDL receptor mRNA expression in nontransgenic, human cholesteryl ester transfer protein (CETP) transgenic, and human apolipoprotein (Apo) B/CETP double transgenic mice fed a normal chow diet and a high fat, high cholesterol diet (HFHC). Three weeks of HFHC feeding increased total serum cholesterol 1.5-fold in the nontransgenic, 3.1-fold in the CETP transgenic, and 3.4-fold in the ApoB/CETP double transgenic mice. To examine the liver LDL receptor mRNA expression among the different groups of mice fed the normal diet or fed the HFHC diet, we developed a quantitative reverse-transcribed polymerase chain reaction assay in which the LDL receptor mRNA level was normalized with the ß-actin mRNA. The results show that on the normal chow diet, the LDL receptor mRNA expression levels were lower in the ApoB/CETP mice than in the nontransgenic mice and the human CETP transgenic mice. Liver LDL receptor gene expression was lower in all groups of mice fed the HFHC diet, with the lowest level of expression in the ApoB/CETP mice. Similar results were obtained by Northern blot analysis. In addition, we have previously shown that the cytokine oncostatin M (OM) increases LDL receptor gene expression in HepG2 cells. In this study, we used the ApoB/CETP mice as the model system to examine the in vivo activity of OM on liver LDL receptor gene expression. Our data show that OM increased the level of liver LDL receptor mRNA up to 80% to 90% when the animals were fed the HFHC diet. The results from these studies demonstrate that the expression of the liver LDL receptor in the ApoB/CETP mice is suppressed compared with nontransgenic mice and that the expression of the hepatic LDL receptor gene in these mice is subjected to the normal cholesterol feedback regulation. In addition, LDL receptor gene expression in these mice is also inducible by a positive regulator.

Key Words: LDL • LDL receptor • serum cholesterol • transgenic mice • oncostatin M

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