Altered hepatic fatty acid metabolism in endotoxicosis: effect of L-carnitine on survival

Abstract

The activities of palmitoyl-coenzyme A (CoA) synthetase, carnitine acetyltransferase (CAT), and carnitine palmitoyltransferase (CPT) and the levels of ketone bodies, reduced coenzyme A (CoASH), carnitine, and their esters, which are involved in fatty acid metabolism, in rat liver and plasma were measured after the administration of Escherichia coli lipopolysaccharide (LPS). We also studied the effect of L-carnitine treatment before LPS administration on survival and on hepatic fatty acid metabolism. The activities of CAT and CPT and the concentrations of ketone bodies, CoA, and carnitine derivatives (except for malonyl-CoA) declined in the liver after LPS administration. The activity of palmitoyl-CoA synthetase was changed little after LPS administration, and the level of hepatic malonyl-CoA increased significantly, suggesting that LPS causes activated fatty acids to undergo esterification and lipogenesis rather than oxidation. Treatment of rats with L-carnitine before LPS greatly increased the survival rate, but did not affect enzymes that metabolize fatty acids, CoA, or carnitine derivatives in the liver. Further studies are necessary to elucidate the mechanism of the effect of carnitine on post-LPS survival.

Accelerated Hepatic Lipid Synthesis in Fasted Septic Rats

“…Hence, an increased hepatic citrate content after CLP and a decreased hepatic long-chain acyl-CoA content after in vivo LPS administration [3] may promote the dephosphorylation of acetyl-CoA carboxylase. The increased malonylCoA content of frozen liver samples obtained from the septic rats may be a consequence of such an increase in acetyl-C'oA carboxylase activity.…”

“…However, increased hepatic VLDL production and secretion may also play a role [3,4,6], A recent in vitro study by Victorov et al [6] showed that incubation with LPS significantly increased hepatocyte TG production and secretion independent of the influence of extrahepatic factors like hor mones, cytokines, and free fatty acids (FFA). We also recently found [3] that LPS adminis tration reduced hepatic carnitine palmitoyl transferase (CPT; EC 2.3.1.21) activity and raised the hepatic content of malonyl-coenzyme A (CoA). the first intermediate in lipogenesis catalyzed by acetyl-CoA carboxylase and a potent CPT inhibitor [7].…”

“…G6PD activity was determined in the cytosolic fraction at 30 °C [17], CPT activity in the mitochon drial fraction was assayed spectrophotometrically by measuring the initial rates of total CoASH formation from palmitoyl-CoA with 5,5'-dithiobis-(2-nitrobenzoate)(DTNB) at 412 nm [3], A molar extinction coef ficient of 13.600 cm-1 for DTNB at pH 8.0 was used.…”

“…Malonyl-CoA and citrate levels were mea sured in the neutralized perchloric acid supernatant of frozen liver. Malonyl-CoA was assayed by reversedphase HPLC after enrichment and purification on a Sep-Pak Cl* minicolumn [3], The hepatic concentra tions of citrate [20] and protein, and the plasma con centrations of TG, glucose, FFA, and albumin were assayed by standard spectrophotometric procedures [3], Insulin concentrations were determined by ra dioimmunoassay [21].…”

Gluconeogenesis and Phosphoenergetics in Rat Liver during Endotoxemia

“…After the cessation of infusion, the alanine level decreased and reached approx highest. Plasma glucagon levels in the ETX(/) groups a 70% lethal dose at 24 h [26]. During the observation period, the endotoxin caused hyperglycemia and tachycardia without hypotension.…”