Inverse Relationship Between Peroxisomal and Mitochondrial  -Oxidation in HepG2 Cells Treated with Dehydroepiandrosterone and Clofibric Acid

Abstract

A transformed human hepatoma cell line was examined to determine if it was an appropriate model system for studying the mechanism of action of two peroxisome proliferators that lower blood lipids. Cultures of HepG2 cells were exposed to four different concentrations of either the hypolipidemic drug, clofibric acid (CLO), or the adrenal steroid, dehydroepiandrosterone (DHEA). Activities of two peroxisomal enzymes, palmitoyl-CoA oxidase and catalase, and two mitochondrial enzymes, carnitine palmitoyl-CoA transferase and succinate-INT-reductase, were measured in CLO- and DHEA-treated cells. In general, as the concentration of these hypolipidemic agents increased from 0 to 1000 microM, the specific activities of peroxisomal palmitoyl-CoA oxidase and catalase increased, and mitochondrial carnitine palmitoyl-CoA transferase and succinate-INT-reductase decreased. The activity of lactate dehydrogenase was significantly higher in the medium of cultures exposed to the 500 and 1000 microM concentration of DHEA compared with the control cultures, indicating the cytotoxic effects of this steroid at millimolar levels in vitro. In summary, the peroxisomal proliferators, DHEA and CLO, inversely altered peroxisomal and mitochondrial beta-oxidation in HepG2 cultures, but not to the extent reported for rat hepatocytes in vitro. In vitro concentrations of DHEA greater than 500 microM adversely affected the viability of HepG2 cells. The results of this study suggest that beta-oxidation in this human hepatoma cell line may not be as sensitive to hypolipidemic agents as are primary cultures of rat hepatocytes.

Voluntary exercise and green tea enhance the expression of genes related to energy utilization and attenuate metabolic syndrome in high fat fed mice

“…Acox1 expression in the skeletal muscle was decreased in all treatment groups. Acox1 is involved in peroxisomal β‐oxidation, and previous studies have demonstrated that the expression of Acox1 is inversely associated with gene expression related to mitochondrial β‐oxidation .…”

PPARα agonists clofibrate and gemfibrozil inhibit cell growth, down-regulate hCG and up-regulate progesterone secretions in immortalized human trophoblast cells

“…In regard to the effect of PPARα agonist on peroxisomal enzymes and proliferation, there are many reports about rat liver [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]. In human liver cells, some reports revealed an increase in peroxisomal enzyme activity caused by PPARα agonist [5,6,10,12,19], while others found no effect [2,3,8,9,14]. In all organs except the liver, the effects of PPARα agonist on peroxisomes are little reported in rats [17], and even less so in humans [21].…”

Dehydroepiandrosterone sulfate and beta-cell function: enhanced glucose-induced insulin secretion and altered gene expression in rodent pancreatic beta-cells.

“…The modest elevation of LC-CoA noted in these preliminary experiments may be related to the variability of cellular LC-CoA pool sizes, with the larger mitochondrial pool showing no increase in LC-CoA and the smaller cytoplasmic pool increasing (14). Although we did not assess the expression of carnitine palmitoyl transferase (CPT)-1, other authors have found a DHEA-induced decrease in the hepatic activity of this enzyme, which would further increase cytoplasmic LC-CoA levels (39). The expression of ACS(2) mRNA is elevated by 24 h although the effect on insulin secretion is not seen until 3 days.…”

“…by DHEA and DHEAS in Zucker rat liver, cultured Wistar rat hepatocytes, and the HepG2 liver cell line (13,14,39). These enzymes are involved in the regulation of lipid ␤-oxidation by the mitochondria and peroxisomes, and ACS also controls flux into lipid synthetic pathways.…”