Increased hepatic mitochondrial FA oxidation reduces plasma and liver TG levels and is associated with regulation of UCPs and APOC-III in rats

• Published in: Journal of lipid research 2017-07, Vol.58 (7), p.1362-1373
• Main Authors: Lindquist, Carine, Bjørndal, Bodil, Rossmann, Christine Renate, Tusubira, Deusdedit, Svardal, Asbjørn, Røsland, Gro Vatne, Tronstad, Karl Johan, Hallström, Seth, Berge, Rolf Kristian
• Format: Article
• Language: English
• Subjects: 2-(tridec-12-yn-1-ylthio)acetic acid; Acetic acid; Acetic Acid - chemistry; Acetic Acid - pharmacology; Acetylcarnitine - metabolism; AMP; Animals; apolipoprotein C-III; Apolipoprotein C-III - metabolism; Carnitine - metabolism; Cytochrome c; Energy Metabolism - drug effects; fatty acid; fatty acid metabolism; Fatty Acids - metabolism; Gene expression; Ketones; lipids; lipids/oxidation; Lipoprotein lipase; lipoproteins; Lipoproteins (very low density); Liver; Liver - drug effects; Liver - metabolism; Male; metabolic syndrome; mitochondria; Mitochondria, Liver - drug effects; Mitochondria, Liver - metabolism; Mitochondrial DNA; Mitochondrial uncoupling protein 2; Mitochondrial Uncoupling Proteins - metabolism; nonalcoholic fatty liver disease; Oxidation; Oxidation-Reduction; Rats; Rats, Wistar; Rodents; triglyceride; Triglycerides - blood; Triglycerides - metabolism; uncoupling protein
• ISSN: 0022-2275; 1539-7262
• DOI: 10.1194/jlr.M074849

Hepatic mitochondrial function, APOC-III, and LPL are potential targets for triglyceride (TG)-lowering drugs. After 3 weeks of dietary treatment with the compound 2-(tridec-12-yn-1-ylthio)acetic acid (1-triple TTA), the hepatic mitochondrial FA oxidation increased more than 5-fold in male Wistar rats. Gene expression analysis in liver showed significant downregulation of APOC-III and upregulation of LPL and the VLDL receptor. This led to lower hepatic (53%) and plasma (73%) TG levels. Concomitantly, liver-specific biomarkers related to mitochondrial biogenesis and function (mitochondrial DNA, citrate synthase activity, and cytochrome c and TFAM gene expression) were elevated. Interestingly, 1-triple TTA lowered plasma acetylcarnitine levels, whereas the concentration of β-hydroxybutyrate was increased. The hepatic energy state was reduced in 1-triple TTA-treated rats, as reflected by increased AMP/ATP and decreased ATP/ADP ratios, whereas the energy state remained unchanged in muscle and heart. The 1-triple TTA administration induced gene expression of uncoupling protein (UCP)2 and UCP3 in liver. In conclusion, the 1-triple TTA-mediated clearance of blood TG may result from lowered APOC-III production, increased hepatic LPL gene expression, mitochondrial FA oxidation, and (re)uptake of VLDL facilitating drainage of FAs to the liver for β-oxidation and production of ketone bodies as extrahepatic fuel. The possibility that UCP2 and UCP3 mediate a moderate degree of mitochondrial uncoupling should be considered.