Drainage of fatty acids from blood in a liver-specific manner -associated with increased hepatic mitochondrial fatty acid oxidation, lowering triacylglycerol levels in liver and plasma.

Hepatic mitochondrial function, apolipoproteinC-III and lipoprotein lipase are potential targets for triacylglycerol lowering drugs. We wanted to investigate whether a new drug could influence these parameters. After dietary treatment of male Wistar rats with 100mg/kg body weight of the compound 2-(tetradec-12-yn-1-ylthio)acetic acid (triple-TTA) for three weeks, the hepatic mitochondrial fatty acid oxidation increased 5-fold. Gene expression analysis in liver showed significant downregulation of ApoC-III, and upregulation of Lpl and Vldlr,. Hepatic and plasma triacylglycerol were reduced, accompanied by induction of liver-specific mitochondrial biomarkers such as mitochondrial DNA, cytochrome c and mitochondrial transcription factor A. Interestingly, triple-TTA lowered the plasma acetylcarnitine level whereas the concentration of betahydroxybutyrate was increased. The hepatic energy charge was lowered in triple-TTA treated rats, as reflected by increased AMP/ATP ratio, whereas energy charge remained unchanged in muscle and heart. Triple-TTA administration induced gene expression of uncoupling proteins 2 and 3 in liver. Altogether, triple-TTA may induce (re)uptake of VLDL to the liver, facilitating drainage of lipids from the blood to liver for beta oxidation and production of ketone bodies as extrahepatic fuel. The possibility that UCP2/3 mediate a moderate degree of mitochondrial uncoupling and thereby protect against ROS production should be considered.