Effects of MET-88, a .GAMMA.-Butyrobetaine Hydroxylase Inhibitor, on Tissue Carnitine and Lipid Levels in Rats.

Abstract

MET-88, 3-(2,2,2-trimethylhydrazinium) propionate, suppresses carnitine synthesis by inhibiting (gamma-butyrobetaine hydroxylase. The purpose of this study was to clarify the effects of suppression of carnitine synthesis on carnitine and lipid contents in tissues. MET-88 (50, 100, 200 or 400 mg/kg/d) was administered orally to male SD rats for 10, 30 or 60 d. Total carnitine and lipid (triglycerides, non-esterified fatty acids) contents were measured in heart and liver. In both tissues, treatment with MET-88 dose-dependently decreased total carnitine levels, and the reduction reached the plateau state after 30 d at each dose. MET-88 had no effect on lipid content in the heart, but increased the lipid content in the liver at the highest doses. Treatment with MET-88 at 400 mg/kg for 60 d resulted in no pathologic findings in the histological study, and also had no effect on parameters of liver function such as glutamic-oxaloacetic transaminase and glutamic-pyruvic transaminase as judged from the results of blood biochemical analysis. We concluded that long-term treatment with MET-88 decreased the carnitine content to a constant level in both heart and liver, but had no effect on lipid contents in the heart, although it affected lipid metabolism in the liver.

Mechanisms of liver steatosis in rats with systemic carnitine deficiency due to treatment with trimethylhydraziniumpropionate

“…2 , and in agreement with previous studies (12,13), rats treated with THP for 3 weeks developed micro-and macrovesicular liver steatosis predominantly in zone I and II of the liver lobules. Similar findings were obtained after 6 weeks of treatment with THP (results not shown).…”

“…by guest, on May 12, 2018 www.jlr.org Downloaded from explanation). Peroxisomal proliferation may result from stimulation of PPAR␣ by accumulated fatty acids and fatty acid derivatives in THP-treated rats (42), and may represent a mechanism to compensate for decreased mitochondrial metabolism of fatty acids.…”

“…by guest, on May 12, 2018 www.jlr.org Downloaded from acid soluble (supernatant) and an acid insoluble fraction (pellet). The acid soluble fraction is used to measure free and acetyl-CoA and, after alkaline hydrolysis, total acid soluble CoA.…”

“…In this model, carnitine deficiency is induced within 3 weeks by feeding trimethylhydraziniumpropionate (THP), which inhibits carnitine biosynthesis and increases renal excretion of carnitine. Interestingly, rats treated with THP develop combined micro-and macrovesicular liver steatosis within 3 weeks but have no macro-or microscopic accumulation of lipids in skeletal muscle or heart (12,13). Since carnitine is essential for transport of long-chain fatty acids into the mitochondrial matrix (14), it can be speculated that at least the microvesicular part of liver steatosis in THP-treated rats could be caused by hepatic carnitine deficiency.…”

Mildronate, a Regulator of Energy Metabolism, Reduces Atherosclerosis in apoE/LDLR^–/– Mice

“…Inhibition of L -carnitine synthesis and its reabsorption leads to decreased L -carnitine concentrations in plasma and organs such as the heart, liver and brain [15,16] . In turn, the decreased L -carnitine concentration results in decreased long-chain fatty acid ␤ -oxidation [13,17] .…”