Developmental and Pharmacological Regulation of Apolipoprotein C-II Gene Expression

Abstract

Abstract-Increased plasma triglyceride concentrations are often observed in metabolic disorders predisposing to coronary heart disease. Among the major determinants of plasma triglyceride metabolism are the apolipoproteins (apos) of the C class, C-I, C-II, and C-III. Whereas physiological concentrations of apo C-II are required for lipolysis of triglycerides by lipoprotein lipase (LPL), overexpression of all 3 C apolipoproteins leads to hypertriglyceridemia. In the present study, we investigated apo C-II gene regulation under conditions associated with profound changes in plasma triglyceride metabolism, ie, during postnatal development and after treatment with the triglyceride-lowering fibrate drugs, and compared its expression to that of apo C-I and apo C-III. Whereas the expression of both apo C-I and apo C-III is low in fetal liver, increases gradually after birth, and attains maximal levels after weaning, apo C-II gene expression is already detectable in the fetal liver, increases rapidly immediately after birth, and remains elevated throughout suckling. Thus, the increased ingestion of lipids during suckling is met by an earlier induction of apo C-II, the obligatory activator for LPL, compared with apo C-III and apo C-I, which antagonize triglyceride catabolism. Treatment of rats with fibrates decreased apo C-II gene expression in the liver, but not in the intestine, whereas apo C-I gene expression did not change. The decrease of liver apo C-II mRNA levels after fenofibrate occurred in a time-and dose-dependent manner and was reversible but appeared less pronounced than the decrease of apo C-III mRNA. Apo C-II mRNA levels were not affected after treatment with BRL49653, a peroxisome proliferator-activated receptor (PPAR)␥-specific ligand, suggesting that fibrates act on apo C-II expression via PPAR␣. Addition of fenofibric acid to primary rat and human hepatocytes resulted in a decrease of apo C-II expression. In conclusion, fibrates decrease gene expression of apo C-II and apo C-III, but not apo C-I, in rat and human hepatocytes. This decrease of apo C-II and apo C-III gene expression, together with a lowered apo C-III to apo C-II ratio, should result in an improved clearance of triglyceride-rich remnant lipoproteins from plasma, without hampering triglyceride lipolysis by LPL.

Identification of hepatic transcriptional changes in insulin-resistant rats treated with peroxisome proliferator activated receptor-alpha agonists

“…Apo-CII has an important role as activator of lipoprotein lipase, and patients with Apo-CII deficiency are afflicted with severe hypertriglyceridemia (Breckenridge et al 1978). In contrast to the observed upregulation of Apo-CII in the present study, this gene has previously been reported to be slightly downregulated by fenofibrate in primary human hepatocytes (Andersson et al 1999), which indicates a more complex regulatory mechanism of this gene in vivo. Cyp4A-10 (microsomal -hydroxylation), which is a known PPAR-target (Bell et al 1993), was the most highly drug-induced clone identified, and this gene is, like PPAR-itself, downregulated by the high-fat diet (Fig.…”

Effective kinetics of schisandrin B on serum/hepatic triglyceride and total cholesterol levels in mice with and without the influence of fenofibrate

“…Pharmacological investigations have indicated that the ability of fenofibrate to reduce hepatic and serum lipid levels may be related to several biochemical actions. In essence, fenofibrate was found to stimulate the lipolysis and the elimination of triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing the production of apolipoprotein C-III, an inhibitor of lipoprotein lipase activity, as well as inducing enzymes for catalyzing β-oxidation of fatty acids in mitochondria (Andersson et al 1999;Miura et al 2005). Unlike fenofibrate which could decrease serum total cholesterol level, schisandrin B did not produce any effect in this regard.…”

Fatty acids as regulators of lipid metabolism

“…ApoC-III inhibits the hydrolysis of triacylglycerols by LPL [80] and the apoE mediated clearance of chylomicron remnants by hepatocytes. The suppression of human apoC-III in transgenic mice by the PPARα activator nafenopin led to the suggestion that the decreased inhibition of LPL increased triacylglycerol clearance from blood [80,81]. The mechanism of this negative regulation, however, has not been resolved yet.…”