L‐carnitine prevents metabolic steatohepatitis in obese diabetic KK‐A^y mice

Abstract

Aim: Pharmacological treatment for metabolic syndromerelated non-alcoholic steatohepatitis has not been established. We investigated the effect of L-carnitine, an essential substance for β-oxidation, on metabolic steatohepatitis in mice. Methods:Male KK-A y mice were fed a high-fat diet (HFD) for 8 weeks, with supplementation of L-carnitine (1.25 mg/mL) in drinking water for the latter 4 weeks.Results: Serum total carnitine levels were decreased following HFD feeding, whereas the levels were reversed almost completely by L-carnitine supplementation. In mice given L-carnitine, exacerbation of hepatic steatosis and hepatocyte apoptosis was markedly prevented even though HFD feeding was continued. Body weight gain, as well as hyperlipidemia, hyperglycemia, and hyperinsulinemia, following HFD feeding were also significantly prevented in mice given L-carnitine. High-fat diet feeding elevated hepatic expression levels of carnitine palmitoyltransferase 1A mRNA; however, production of β-hydroxybutyrate in the liver was not affected by HFD alone.In contrast, L-carnitine treatment significantly increased hepatic β-hydroxybutyrate contents in HFD-fed mice. L-carnitine also blunted HFD induction in sterol regulatory element binding protein-1c mRNA in the liver. Furthermore, L-carnitine inhibited HFD-induced serine phosphorylation of insulin receptor substrate-1 in the liver. L-carnitine decreased hepatic free fatty acid content in 1 week, with morphological improvement of swollen mitochondria in hepatocytes, and increases in hepatic adenosine 5'-triphosphate content.Conclusions: L-carnitine ameliorates steatohepatitis in KK-A y mice fed an HFD, most likely through facilitating mitochondrial β-oxidation, normalizing insulin signals, and inhibiting de novo lipogenesis in the liver. It is therefore postulated that supplementation of L-carnitine is a promising approach for prevention and treatment of metabolic syndrome-related non-alcoholic steatohepatitis.

Levocarnitine does not impair chemotherapy cytotoxicity against acute lymphoblastic leukemia

“…Supplemented mice had significantly higher free carnitine concentrations at time of sacrifice than non-supplemented mice (44.3±5.0 vs. 39.7±4.9 μM, p=0.04). Though a modest difference, other studies supplementing mice with similar doses of LC report variability in the effect on serum/ plasma carnitine levels, ranging between approximately 0.65 to 20 μM higher [32][33][34][35].…”

Possible role ofl‐carnitine in improvement of metabolic and hepatic changes in hyperuricemic and hyperuricemic—Fructose‐supplemented rats

“…In the current study, cotreatment of l ‐Carnitine with hyperuricemia induction ameliorated such carbohydrate metabolic derangement, despite not altering the insulin level compared to the untreated hyperuricemic rats, in line with Samimi et al (). Such protective effects of l ‐Carnitine could be mediated by preventing the rise of serine phosphorylation of IRS‐1, which negatively regulates insulin signaling (Kon et al, ). Also, l ‐Carnitine could increase the efflux of acyl and acetyl groups out of the cells into the plasma, reducing the accumulation of these intermediate products of β‐oxidation (Chapela, Kriguer, Fernández, & Stella, ), improving insulin resistance (Zhang, Keung, Samokhvalov, Wang, & Lopaschuk, ).…”

Rifaximin prevents ethanol-induced liver injury in obese KK-Ay mice through modulation of small intestinal microbiota signature

“…KK-A y mice are a congenic strain in which the A y allele at the agouti locus had been transferred to the inbred KK strain by repetitive backcrossing. KK-A y mice are a suitable model of steatohepatitis with metabolic syndrome because they spontaneously become obese and develop hyperglycemia, hyperinsulinemia, and steatohepatitis (28,55,62). We have recently reported that NIAAA model using KK-A y mice exhibits more prominent steatohepatitis than in C57BL/6 mice.…”