Opposite regulation of human versus mouse apolipoprotein A-I by fibrates in human apolipoprotein A-I transgenic mice.

Abstract

The regulation of liver apolipoprotein (apo) A-I gene expression by fibrates was studied in human apo A-I transgenic mice containing a human genomic DNA fragment driving apo A-I expression in liver. Treatment with fenofibrate (0.5% wt/wt) for 7 d increased plasma human apo A-I levels up to 750% and HDL-cholesterol levels up to 200% with a shift to larger particles. The increase in human apo A-I plasma levels was time and dose dependent and was already evident after 3 d at the highest dose (0.5% wt/wt) of fenofibrate. In contrast, plasma mouse apo A-I concentration was decreased after fenofibrate in nontransgenic mice. The increase in plasma human apo A-I levels after fenofibrate treatment was associated with a 97% increase in hepatic human apo A-I mRNA, whereas mouse apo A-I mRNA levels decreased to 51%. In nontransgenic mice, a similar down-regulation of hepatic apo A-I mRNA levels was observed. Nuclear run-on experiments demonstrated that the increase in human apo A-I and the decrease in mouse apo A-I gene expression after fenofibrate occurred at the transcriptional level. Since part of the effects of fibrates are mediated through the nuclear receptor PPAR (peroxisome proliferator-activated receptor), the expression of the acyl CoA oxidase (ACO) gene was measured as a control of PPAR activation. Both in transgenic and nontransgenic mice, fenofibrate induced ACO mRNA levels up to sixfold. When transgenic mice were treated with gemfibrozil (0.5% wt/wt) plasma human apo A-I and HDL-cholesterol levels increased 32 and 73%, respectively, above control levels. The weaker effect of this compound on human apo A-I and HDL-cholesterol levels correlated with a less pronounced impact on ACO mRNA levels (a threefold increase) suggesting that the level of induction of human apo A-I gene is related to the PPAR activating potency of the fibrate used. Treatment of human primary hepatocytes with fenofibric acid (500 M) provoked an 83 and 50% increase in apo A-I secretion and mRNA levels, respectively, supporting that a direct action of fibrates on liver human apo A-I production leads to the observed increase in plasma apo A-I and HDLcholesterol. ( J. Clin. Invest. 1996. 97:2408-2416.)

Role of Esrrg in the fibrate-mediated regulation of lipid metabolism genes in human ApoA-I transgenic mice

“…41 This study shows that the in vivo regulation of the human apoA-I gene in mice when it contains its proximal and distal regulatory sequences resembles the regulation of the mouse Apoa1 gene described previously. 20 The observed differences between the present and the previous studies, 20,23,24 can be explained based on the mechanism of transcriptional regulation of the human APOA-I gene that emerged from in vitro and in vivo studies. 25 In the transgenic mice used here, the expression of the human APOA-I gene was controlled by the proximal promoter and the distal APOCIII enhancer.…”

“…Two previous studies suggested that fenofibrate caused 2-to 2.6-fold increase in human APOA-I gene expression in ApoA-I transgenic mice, as well as a 3.5-to 7.5-fold increase in plasma ApoA-I levels. 20,23 These increases did not occur in ApoA-I transgenic mice in the PPARa-deficient background. 23 In ApoA-I transgenic rabbits, the higher doses of fenofibrate used increased hepatic human ApoA-I mRNA levels and plasma ApoA-I levels approximately 1.6-and 2-fold, respectively.…”

“…24 It has been reported that fenofibrate downregulates the expression of Apoa1 gene in mice, whereas they upregulate the expression of the human ApoA-I. 20 The different responses of the human and mouse Apoa1 genes to the fenofibrate treatment was attributed to differences between the human and rodent Apoa1 promoter. 41 This study shows that the in vivo regulation of the human apoA-I gene in mice when it contains its proximal and distal regulatory sequences resembles the regulation of the mouse Apoa1 gene described previously.…”

“…9,10 Fibrates were shown to promote b-oxidation of fatty acids (FA) by upregulating various genes, including several genes of FA uptake and b-oxidation. [11][12][13][14][15][16][17][18][19] In rodents, fibrates downregulated the expression of Apoa1, 20 hepatic lipase 13 and lecithin cholesterol acyltransferase (Lcat) 15 genes and upregulated the expression of Apoa2 21 and phospholipid transfer protein (Pltp). 22 Previous studies of human ApoA-I transgenic Mice and rabbits indicated that fenofibrate increase plasma ApoA-I and HDL levels.…”

“…The animal models used in these studies carry the human transgene under the control of its proximal promoter and also express their endogenous ApoA-I gene. 20,23,24 To obtain insights on the global molecular changes (34 000 genes) that contribute to lipid lowering and HDL raising effects of fenofibrate, we used a new human ApoA-I mouse model that expresses the human APOA-I gene under the control of the proximal promoter and distal enhancer sequences, in the background of Apoa1-deficient mice.…”