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Int J Mol Sci. 2019 Sep 5;20(18). pii: E4359. doi: 10.3390/ijms20184359.

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

Author information

1
Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), 2333 CK Leiden, The Netherlands. Kanita.salic@tno.nl.
2
Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), 2333 CK Leiden, The Netherlands. Eveline.gart@tno.nl.
3
Human and Animal Physiology, Wageningen University, 6708 WD Wageningen, The Netherlands. Eveline.gart@tno.nl.
4
Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), 2333 CK Leiden, The Netherlands. Florine.seidel@tno.nl.
5
Department of Microbiology and Systems Biology, The Netherlands Organization for Applied Scientific Research (TNO), 3704 HE Zeist, The Netherlands. Lars.Verschuren@tno.nl.
6
Department of Microbiology and Systems Biology, The Netherlands Organization for Applied Scientific Research (TNO), 3704 HE Zeist, The Netherlands. Martien.caspers@tno.nl.
7
Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), 2333 CK Leiden, The Netherlands. Wim.vanduyvenvoorde@tno.nl.
8
Metabolon Inc., Morrisville, NC 27560, USA. KWong@metabolon.com.
9
Human and Animal Physiology, Wageningen University, 6708 WD Wageningen, The Netherlands. Jaap.keijer@wur.nl.
10
Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), 2333 CK Leiden, The Netherlands. Ivana.bobeldijk@tno.nl.
11
Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), 2333 CK Leiden, The Netherlands. WielingaPeter@prahs.com.
12
Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), 2333 CK Leiden, The Netherlands. Robert.kleemann@tno.nl.
13
Department of Vascular Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands. Robert.kleemann@tno.nl.

Abstract

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% w/w), nicotinamide riboside (NR; 0.3% w/w) 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.

KEYWORDS:

acylcarnitines; lipid peroxidation; metabolomics; mitochondria; non-alcoholic fatty liver disease; obesity; transcriptomics; β-oxidation

PMID:
31491949
DOI:
10.3390/ijms20184359
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