Combined Treatment with L-Carnitine and Nicotinamide Riboside Improves Hepatic Metabolism and Attenuates Obesity and Liver Steatosis

• Published in: International journal of molecular sciences Vol. 20; no. 18; p. 4359
• Main Authors: Salic, Kanita, Gart, Eveline, Seidel, Florine, Verschuren, Lars, Caspers, Martien, van Duyvenvoorde, Wim, Wong, Kari E, Keijer, Jaap, Bobeldijk-Pastorova, Ivana, Wielinga, Peter Y, Kleemann, Robert
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 05.09.2019; MDPI
• Subjects: acylcarnitines; Alanine; Alanine transaminase; Animals; Attenuation; Biomarkers; Blood glucose; Body fat; Body weight; Carnitine; Carnitine - pharmacology; Cholesterol; Diet; Disease Models, Animal; Energy metabolism; Energy Metabolism - drug effects; Fatty liver; Fatty Liver - drug therapy; Fatty Liver - genetics; Fatty Liver - metabolism; Food intake; Gene Expression Regulation; High density lipoprotein; Insulin; Insulin resistance; Lipid Metabolism - drug effects; Lipid peroxidation; Lipids; Liver; Low density lipoprotein receptors; Male; Metabolism; Metabolites; Metabolomics; Mice; Mice, Knockout; mitochondria; Niacinamide - analogs & derivatives; Niacinamide - pharmacology; Nicotinamide; non-alcoholic fatty liver disease; Obesity; Obesity - drug therapy; Obesity - genetics; Obesity - metabolism; Oxidation; Oxidative Stress; Pyridinium Compounds; Risk analysis; Risk factors; Signal Transduction; Steatosis; transcriptomics; Triglycerides; Weight control; β-oxidation; non-alcoholic fatty liver disease; metabolomics; mitochondria; transcriptomics; β-oxidation; acylcarnitines; lipid peroxidation; obesity
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms20184359

Obesity characterized by adiposity and ectopic fat accumulation is associated with the development of non-alcoholic fatty liver disease (NAFLD). Treatments that stimulate lipid utilization may prevent the development of obesity and comorbidities. This study evaluated the potential anti-obesogenic hepatoprotective effects of combined treatment with L-carnitine and nicotinamide riboside, i.e., components that can enhance fatty acid transfer across the inner mitochondrial membrane and increase nicotinamide adenine nucleotide (NAD+) levels, which are necessary for β-oxidation and the TCA cycle, respectively. Ldlr -/-.Leiden mice were treated with high-fat diet (HFD) supplemented with L-carnitine (LC; 0.4% / ), nicotinamide riboside (NR; 0.3% / ) or both (COMBI) for 21 weeks. L-carnitine plasma levels were reduced by HFD and normalized by LC. NR supplementation raised its plasma metabolite levels demonstrating effective delivery. Although food intake and ambulatory activity were comparable in all groups, COMBI treatment significantly attenuated HFD-induced body weight gain, fat mass gain (-17%) and hepatic steatosis (-22%). Also, NR and COMBI reduced hepatic 4-hydroxynonenal adducts. Upstream-regulator gene analysis demonstrated that COMBI reversed detrimental effects of HFD on liver metabolism pathways and associated regulators, e.g., ACOX, SCAP, SREBF, PPARGC1B, and INSR. Combination treatment with LC and NR exerts protective effects on metabolic pathways and constitutes a new approach to attenuate HFD-induced obesity and NAFLD.