Developmental and pharmacological regulation of apolipoprotein C-II gene expression - Comparison with apo C-I and apo C-III gene regulation

Increased plasma triglyceride concentrations are often observed in metaboli c disorders predisposing to coronary heart disease. Among the major determi nants of plasma triglyceride metabolism are the apolipoproteins (apos) of t he C class, C-I, C-II, and C-m. Whereas physiological concentrations of apo C-II are required for lipolysis of triglycerides by Lipoprotein lipase (LP L), overexpression of all 3 C apolipoproteins leads to hypertriglyceridemia . Ln the present study, we investigated apo C-II gene regulation under cond itions 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-m. Whereas the expression of both apo C-I and apo C-III is low in fet al 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 throughou t suckling. Thus, the increased ingestion of lipids during suckling is met by an earlier induction of apo C-II, the obligatory activator for LPL, comp ared 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 l iver, but not in the intestine, whereas apo C-I gene expression did not cha nge. 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 p ronounced than the decrease of apo C-III mRNA. Apo C-LT mRNA levels were no t affected after treatment with BRL49653, a peroxisome proliferator-activat ed receptor (PPAR)gamma-specific ligand, suggesting that fibrates act on ap o C-II expression via PPAR alpha. Addition of fenofibric acid to primary ra t and human hepatocytes resulted in a decrease of apo C-II expression. In c onclusion, fibrates decrease gene expression of apo C-II and apo C-m, but n ot apo C-I, in rat and human hepatocytes, This decrease of apo C-II and apo c-m gene expression, together with a lowered apo C-m to apo C-II. ratio, s hould result in an improved clearance of triglyceride-rich remnant lipoprot eins from plasma, without hampering triglyceride lipolysis by LPL.