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Editorial
The Role of Carnitine Orotate Complex in Fatty Liver
Hyon-Seung Yiorcid
Diabetes & Metabolism Journal 2021;45(6):866-867.
DOI: https://doi.org/10.4093/dmj.2021.0272
Published online: November 22, 2021
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Laboratory of Endocrinology and Immune System, Chungnam National University College of Medicine, Daejeon, Korea

Corresponding author: Hyon-Seung Yi orcid Laboratory of Endocrinology and Immune System, Chungnam National University College of Medicine, 282 Munhwa-ro, Jung-gu, Daejeon 35015, Korea E-mail: jmpbooks@cnu.ac.kr

Copyright © 2021 Korean Diabetes Association

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Carnitine (β-hydroxy-γ-trimethylammonium butyrate), a natural nutrient, primarily acts as an essential cofactor for the mitochondrial β-oxidation of fatty acids by promoting the transport of long-chain fatty acids across the mitochondrial membrane in the form of acyl carnitine esters [1]. The products of β-oxidation are used in the tricarboxylic acid cycle to produce adenosine triphosphate as a form of stored energy. This mechanism is important in diseases related to mitochondrial fatty acids oxidation, in which fatty acyl-coenzyme A accumulate in metabolic organs [2]. Moreover, carnitine protects cells against reactive oxygen species induced by mitochondrial stress or DNA damage, which leads to inhibition of mitochondria-dependent apoptosis [3,4].
Orotate, a precursor in biosynthesis of pyrimidines, is found abundantly in milk produced by cows and other dairy products [5]. Dihydroorotate dehydrogenase, an integral protein in the mitochondrial inner membrane, catalyzes the oxidation of dihydroorotate to orotate, which is then converted to uridine monophosphate by uridine monophosphate synthase [6]. Moreover, orotate is well known to be remarkably increased in many congenital diseases associated with defects of the urea cycle or arginine metabolism [7]. Although orotate has a protective role in cardiovascular diseases [8,9], there has been no study showing the precise mechanism of orotate for the attenuation of metabolic diseases.
In the article titled “Carnitine orotate complex ameliorates insulin resistance and hepatic steatosis through carnitine acetyltransferase pathway,” Hong and Lee [10] investigated whether carnitine-orotate complex attenuates high-fat diet-induced steatosis and insulin resistance in mice. Consistent with their previous investigation using the carnitine-orotate complex [11], the authors showed that carnitine-orotate complex inhibited weight gain and fat volume gain without food intake, as well as improved insulin sensitivity and glucose tolerance in high-fat diet-fed mice. They also found a protective effect of carnitine-orotate complex on liver injury and hepatic fat accumulation in mice with diet-induced obesity. Intriguingly, carnitine-orotate complex increased the expressions of sirtuin 1, peroxisome proliferator-activated receptor-gamma coactivator 1-alpha, and nuclear respiratory factor 1 in the liver of the mice fed with a high-fat diet, which may contribute to the improvement of hepatic steatosis through enhancing fatty acid β-oxidation in the liver. To further define the mechanism of carnitine-orotate complex, Hepa-1c1c cells were treated with carnitine-orotate complex to observe the expression of carnitine acetyltransferase (CrAT). Knockdown of CrAT remarkably reduced carnitine-orotate complex-mediated increases in phosphorylated AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-α (PPARα) in Hepa-1c1c cells. Therefore, they suggest that CrAT is a key factor for carnitine-orotate complex-induced metabolic improvement in mice.
Based on previous studies [10,11], carnitine-orotate complex is regarded as one of the most promising drugs for preventing insulin resistance and metabolic liver disease. Hepatic steatosis progresses to hepatocyte injuries and induces initiation of inflammation, which activates liver-resident immune cells. In other words, the liver is an immunologic organ because of the enrichment of diverse types of immune cells, which are involved in the pathogenesis of fatty liver and advance liver diseases [12]. Therefore, the role of carnitine-orotate complex on the population and activation of hepatic immune cells should be elucidated in the development of non-alcoholic steatohepatitis and liver fibrosis. Moreover, based on the immunomodulatory roles of hepatic stellate cells and bidirectional interactions between hepatic stellate cells and immune cells [12-14], further investigations are needed to identify whether carnitine-orotate complex regulates the activation of hepatic stellate cells. On the other hand, emerging investigations indicated that mitochondrial unfolded protein response and mitokine networks not only inhibit the progression of fatty liver [15,16], but also ameliorate liver fibrosis and injury in mice [17]. Thus, it would be interesting to determine how carnitine-orotate complex affects mitochondrial unfolded protein response and mitokine production, which may regulate the attenuation of fatty liver and advanced liver disease.

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

  • 1. Longo N, Frigeni M, Pasquali M. Carnitine transport and fatty acid oxidation. Biochim Biophys Acta 2016;1863:2422-35.ArticlePubMedPMC
  • 2. Schrader M, Costello J, Godinho LF, Islinger M. Peroxisome-mitochondria interplay and disease. J Inherit Metab Dis 2015;38:681-702.ArticlePubMed
  • 3. Hagen TM, Liu J, Lykkesfeldt J, Wehr CM, Ingersoll RT, Vinarsky V, et al. Feeding acetyl-L-carnitine and lipoic acid to old rats significantly improves metabolic function while decreasing oxidative stress. Proc Natl Acad Sci U S A 2002;99:1870-5.PubMedPMC
  • 4. Pastorino JG, Snyder JW, Serroni A, Hoek JB, Farber JL. Cyclosporin and carnitine prevent the anoxic death of cultured hepatocytes by inhibiting the mitochondrial permeability transition. J Biol Chem 1993;268:13791-8.ArticlePubMed
  • 5. Loffler M, Carrey EA, Zameitat E. Orotate (orotic acid): an essential and versatile molecule. Nucleosides Nucleotides Nucleic Acids 2016;35:566-77.ArticlePubMed
  • 6. Evans DR, Guy HI. Mammalian pyrimidine biosynthesis: fresh insights into an ancient pathway. J Biol Chem 2004;279:33035-8.ArticlePubMed
  • 7. Brosnan ME, Brosnan JT. Orotic acid excretion and arginine metabolism. J Nutr 2007;137(6 Suppl 2):1656S-61S.ArticlePubMed
  • 8. Stepura OB, Martynow AI. Magnesium orotate in severe congestive heart failure (MACH). Int J Cardiol 2009;134:145-7.ArticlePubMed
  • 9. Vilskersts R, Liepinsh E, Kuka J, Cirule H, Veveris M, Kalvinsh I, et al. Myocardial infarct size-limiting and anti-arrhythmic effects of mildronate orotate in the rat heart. Cardiovasc Drugs Ther 2009;23:281-8.ArticlePubMedPDF
  • 10. Hong JH, Lee MK. Carnitine orotate complex ameliorates insulin resistance and hepatic steatosis through carnitine acetyltransferase pathway. Diabetes Metab J 2021;45:933-47.ArticlePubMedPMCPDF
  • 11. Bae JC, Lee WY, Yoon KH, Park JY, Son HS, Han KA, et al. Improvement of nonalcoholic fatty liver disease with carnitineorotate complex in type 2 diabetes (CORONA): a randomized controlled trial. Diabetes Care 2015;38:1245-52.ArticlePubMedPDF
  • 12. Yi HS, Jeong WI. Interaction of hepatic stellate cells with diverse types of immune cells: foe or friend? J Gastroenterol Hepatol 2021;28 Suppl 1:99-104.ArticlePDF
  • 13. Yi HS, Eun HS, Lee YS, Jung JY, Park SH, Park KG, et al. Treatment with 4-methylpyrazole modulated stellate cells and natural killer cells and ameliorated liver fibrosis in mice. PLoS One 2015;10:e0127946.ArticlePubMedPMC
  • 14. Yi HS, Lee YS, Byun JS, Seo W, Jeong JM, Park O, et al. Alcohol dehydrogenase III exacerbates liver fibrosis by enhancing stellate cell activation and suppressing natural killer cells in mice. Hepatology 2014;60:1044-53.ArticlePubMed
  • 15. Moon JS, Goeminne L, Kim JT, Tian JW, Kim SH, Nga HT, et al. Growth differentiation factor 15 protects against the agingmediated systemic inflammatory response in humans and mice. Aging Cell 2020;19:e13195.ArticlePubMedPMCPDF
  • 16. Yi HS. Implications of mitochondrial unfolded protein response and mitokines: a perspective on fatty liver diseases. Endocrinol Metab (Seoul) 2019;34:39-46.ArticlePubMedPMCPDF
  • 17. Chung HK, Kim JT, Kim HW, Kwon M, Kim SY, Shong M, et al. GDF15 deficiency exacerbates chronic alcohol- and carbon tetrachloride-induced liver injury. Sci Rep 2017;7:17238.ArticlePubMedPMCPDF

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        The Role of Carnitine Orotate Complex in Fatty Liver
        Diabetes Metab J. 2021;45(6):866-867.   Published online November 22, 2021
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