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

Abstract

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.

A fatty acid analogue targeting mitochondria exerts a plasma triacylglycerol lowering effect in rats with impaired carnitine biosynthesis

“…However, the combination of Mildronate and 1-triple TTA decreased Bbox1 compared to Mildronate and to some extent control group (p = 0.021). 1-triple TTA treatment in rats has previously been shown to reduce Bbox1 expression and to lower plasma carnitine and acetylcarnitine levels by 40–50%, but also γ-butyrobetaine by 40% [ 25 ]. This suggests different mechanisms: while Mildronate reduces carnitine levels by inhibiting the enzyme involved in carnitine biosynthesis [ 49 ], 1-triple TTA may affect gene expression of Bbox1 and most likely increase carnitine consumption [ 25 ].…”

“…1-triple TTA treatment in rats has previously been shown to reduce Bbox1 expression and to lower plasma carnitine and acetylcarnitine levels by 40–50%, but also γ-butyrobetaine by 40% [ 25 ]. This suggests different mechanisms: while Mildronate reduces carnitine levels by inhibiting the enzyme involved in carnitine biosynthesis [ 49 ], 1-triple TTA may affect gene expression of Bbox1 and most likely increase carnitine consumption [ 25 ]. In the presence of Mildronate, 1-triple TTA showed no additional reduction of plasma carnitine compared to Mildronate (71% vs 85%), but a larger reduction than previously reported with 1-triple TTA alone (52%, Lindquist et al [ 25 ]).…”

“…This suggests different mechanisms: while Mildronate reduces carnitine levels by inhibiting the enzyme involved in carnitine biosynthesis [ 49 ], 1-triple TTA may affect gene expression of Bbox1 and most likely increase carnitine consumption [ 25 ]. In the presence of Mildronate, 1-triple TTA showed no additional reduction of plasma carnitine compared to Mildronate (71% vs 85%), but a larger reduction than previously reported with 1-triple TTA alone (52%, Lindquist et al [ 25 ]). Hence, Mildronate seemed to dominate the carnitine decrease in the combined intervention group.…”

“…The sample preparation and high-performance liquid chromatography measurement of ATP, ADP and AMP were performed as previously described [ 31 – 33 ]. Details are given in Lindquist et al [ 25 ]. Energy charge was calculated employing the following formula: Energy charge = (ATP + 0.5 ADP)/(AMP + ADP + ATP).…”

“…In addition, it has a triple bond at the ω-end making it resistant to both β-oxidation and ω-degradation. 1-triple TTA was introduced by Lindquist et al [ 25 ] as a mitochondrial activator and proliferator in rats. It was demonstrated to increase the hepatic mitochondrial fatty acid oxidation based on in vitro palmitoyl-CoA oxidation assay, enzyme activity assays and gene expression of enzymes involved in mitochondrial β-oxidation and the carnitine shuttle.…”