Beneficial effects of α-lipoic acid in diabetes- and drug- induced liver injury
Keywords:α-lipoic acid, diabetic complications, liver injury, oxidative stress, nonalcoholic fatty liver disease, drug toxicity
Abstract: This review summarizes the effects of α-lipoic acid (LA) on liver damage and complications in diabetes and drug toxicity. LA is a naturally occurring dithiol compound that plays an essential role in mitochondrial metabolism in its protein-bound form. In contrast, free LA in supplements has diverse biological actions, and its antioxidant effect is its most studied and important activity. Due to its strong antioxidant potential, LA could have a promising role in the treatment of pathologies resulting from an imbalance in redox homeostasis. This includes diabetes, which produces deleterious effects on many organs, including the liver. In diabetes specifically, LA prevents β-cell destruction, enhances glucose uptake, and its antioxidant effects may be particularly useful in slowing down the development of diabetic complications. Diabetes-related liver damage is a serious complication in which oxidative stress is the main contributor to tissue injury. Oxidative stress is regarded as one of the main pathological mechanisms underlying liver pathologies provoked by other insults, such as drug toxicity, where LA could also be a useful agent in therapeutic intervention. However, before wider application of LA in a clinical setting, experimental and clinical research needs to be extended.
Received: May 3, 2018; Revised: May 24, 2018; Accepted: May 29, 2018; Published online: June 7, 2018
How to cite this article: Uskoković A, Dinić S, Grdović N, Arambašić-Jovanović J, Vidaković M, Poznanović G, Mihailović M. Beneficial effects of α-lipoic acid in diabetes- and drug- induced liver injury. Arch Biol Sci. 2018;70(4):621-8.
Reed LJ, DeBusk BG, Gunsalus IC, Hornberger CS Jr. Crystalline alpha-lipoic acid; a catalytic agent associated with pyruvate dehydrogenase. Science. 1951;114:93-4.
Ross SM. Clinical applications of lipoic acid in type II diabetes mellitus. Holist Nurs Pract. 2006;20:305-6.
Gomes MB, Negrato CA. Alpha-lipoic acid as a pleiotropic compound with potential therapeutic use in diabetes and other chronic diseases. Diabetol Metab Syndr. 2014;6:80.
Singh U, Jialal I. Alpha-lipoic acid supplementation and diabetes. Nutr Rev. 2008;66:646-57.
Shay KP, Moreau RF, Smith EJ, Smith AR, Hagen TM. Alpha-lipoic acid as a dietary supplement: Molecular mechanisms and therapeutic potential. Biochim Biophys Acta 2009;1790(10):1149-60.
Jones W, Li X, Qu ZC, Perriott L, Whitesell RR, May JM. Uptake, recycling, and antioxidant actions of alpha-lipoic acid in endothelial cells. Free Radic Biol Med. 2002;33:83-93.
Moini H, Packer L, Saris NE. Antioxidant and prooxidant activities of alpha-lipoic acid and dihydrolipoic acid. Toxicol Appl Pharmacol. 2002;182(1):84-90.
Suzuki YJ, Tsuchiya M, Packer L. Thioctic acid and dihydrolipoic acid are novel antioxidants which interact with reactive oxygen species. Free Radic Res Commun. 1991;15:255-63.
Mihailović M, Arambašić J, Uskoković A, Dinić S, Grdović N, Marković J, Poznanović G, Vidaković M. Alpha-lipoic acid preserves the structural and functional integrity of red blood cells by adjusting the redox disturbance and decreasing O-GlcNAc modifications of antioxidant enzymes and heat shock proteins in diabetic rats. Eur J Nutr. 2012;51(8):975-986.
Golbidi S, Badran M, Laher I. Diabetes and alpha lipoic Acid. Front Pharmacol. 2011;2:69.
Bustamante J, Lodge JK, Marcocci L, Tritschler HJ, Packer L, Rihn BH. Alpha-lipoic acid in liver metabolism and disease. Free Radic Biol Med. 1998;24(6):1023-39.
Singh HPP, Bowman RH. Effect of D,L-alpha lipoic acid on the citrate concentration and phosphofructokinase activity of perfused hearts from normal and diabetic rats. Biochem Biophys Res Commun. 1970;41:555-61.
Konrad D, Somwar R, Sweeney G, Yaworsky K, Hayashi M, Ramlal T, Klip A. The antihyperglycemic drug alpha-lipoic acid stimulates glucose uptake via both GLUT4 translocation and GLUT4 activation: potential role of p38 mitogen-activated protein kinase in GLUT4 activation. Diabetes. 2001;50(6):1464-71.
Packer L, Cadenas E. Lipoic acid: energy metabolism and redox regulation of transcription and cell signaling. J Clin Biochem Nutr. 2011;48(1):26-32.
Gupte AA, Bomhoff GL, Morris JK, Gorres BK, Geiger PC. Lipoic acid increases heat shock protein expression and inhibits stress kinase activation to improve insulin signaling in skeletal muscle from high-fat-fed rats. J Appl Physiol. 2009;106(4):1425-34.
Jacob S, Henriksen EJ, Schiemann AL, Simon I, Clancy DE, Tritschler HJ, Jung WI, Augustin HJ, Dietze GJ. Enhancement of glucose disposal in patients with type 2 diabetes by alpha-lipoic acid. Arzneimittelforschung. 1995;45(8):872-4.
Tolman KG, Fonseca V, Dalpiaz A, Tan MH. Spectrum of liver disease in type 2 diabetes and management of patients with diabetes and liver disease. Diabetes Care 2007;30(3):734-43.
Wang K. Molecular mechanisms of hepatic apoptosis. Cell Death Dis. 2014;5:e996.
Li S, Tan HY, Wang N, Zhang ZJ, Lao L, Wong CW, Feng Y. The Role of Oxidative Stress and Antioxidants in Liver Diseases. Int J Mol Sci. 2015;16(11):26087-124.
Nishikawa T, Edelstein D, Du XL, Yamagishi S, Matsumura T, Kaneda Y, Yorek MA, Beebe D, Oates PJ, Hammes HP, Giardino I, Brownlee M. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycemic damage. Nature. 2000;404(6779):787-90.
Brownlee M. (2001). Biochemistry and molecular cell biology of diabetic complications. Nature. 2001;414(6865):813-20.
Dickinson DA, Forman HJ. Cellular glutathione and thiols metabolism. Biochem Pharmacol. 2002a;64(5-6):1019-26.
Dickinson DA, Forman HJ. Glutathione in defense and signaling: lessons from a small thiol. Ann NY Acad Sci. 2002b;973:488-504.
Han D, Handelman G, Marcocci L, Sen CK, Roy S, Kobuchi H, Tritschler HJ, Flohé L, Packer L. Lipoic acid increases de novo synthesis of cellular glutathione by improving cystine utilization. Biofactors. 1997;6(3):321-38.
Suh JH, Shenvi SV, Dixon BM, Liu H, Jaiswal AK, Liu RM, Hagen TM. Decline in transcriptional activity of Nrf2 causes age-related loss of glutathione synthesis, which is reversible with lipoic acid. Proc Natl Acad Sci USA. 2004;101(10):3381-6.
Dinić S, Arambašić J, Mihailović M, Uskoković A, Grdović N, Marković J, Karadžić B, Poznanović G, Vidaković M. Decreased O-GlcNAcylation of the key proteins in kinase and redox signalling pathways is a novel mechanism of the beneficial effect of α-lipoic acid in diabetic liver. Br J Nutr. 2013;110:401-12.
Sadi G, Yılmaz Ö, Güray T. Effect of vitamin C and lipoic acid on streptozotocin-induced diabetes gene expression: mRNA and protein expressions of Cu-Zn SOD and catalase. Mol Cell Biochem. 2008;309(1-2):109-16.
Shay KP, Moreau RF, Smith EJ, Hagen TM. Is alpha-lipoic acid a scavenger of reactive oxygen species in vivo? Evidence for its initiation of stress signaling pathways that promote endogenous antioxidant capacity. IUBMB Life. 2008;60(6):362-7.
Li W, Khor TO, Xu C, Shen G, Jeong WS, Yu S, Kong AN. Activation of Nrf2-antioxidant signaling attenuates NF-κB-inflammatory response and elicits apoptosis. Biochem Pharmacol. 2008;76(11):1485-9.
Patel S, Santani D. Role of NF-B in the pathogenesis of diabetes and its associated complications. Pharmacol. Rep. 2009;61(4):595-603.
Barnes PJ, Karin M. Nuclear factor-kappa B: a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med. 1997;336:1066-71.
Ying Z, Kampfrath T, Sun Q, Parthasarathy S, Rajagopalan S. Evidence that α-lipoic acid inhibits NFκ-B activation independent of its antioxidant function. Inflamm Res. 2011;60:219-25.
Oksala NK, Laaksonen DE, Lappalainen J, Khanna S, Nakao C, Hanninen O, Sen CK, Atalay M. Heat shock protein 60 response to exercise in diabetes: effects of alpha-lipoic acid supplementation. J Diabetes Complicat. 2006;20:257-261.
Arambašić J, Mihailović M, Uskoković A, Dinić S, Grdović N, Marković J, Poznanović G, Bajec Đ, Vidaković M. Alpha-lipoic acid upregulates antioxidant enzyme gene expression and enzymatic activity in diabetic rat kidneys through an O-GlcNAc-dependent mechanism. Eur J Nutr. 2013;52(5):1461-73.
Oksala NK, Lappalainen J, Laaksonen DE, Khanna S, Kaarniranta K, Sen CK, Atalay M. Alpha-lipoic Acid modulates heat shock factor-1 expression in streptozotocin-induced diabetic rat kidney. Antioxid Redox Signal. 2007;9:497-506.
Bernal W, Wendon J. Acute Liver Failure. N Engl J Med. 2013;369:2525-34.
Pandit A, Sachdeva T, Bafna P. Drug-Induced Hepatotoxicity: A Review. J App Pharm Sci. 2012;02(05):233-43.
Russmann S, Kullak-Ublick GA, Grattagliano I. Current concepts of mechanism in drug-induced hepatotoxicity. Curr Med Chem. 2009;16(23):3041-53.
Yuan L, Kaplowitz N. Mechanisms of Drug Induced Liver Injury. Clin Liver Dis. 2013;17(4):507-18.
Andringa KK, Bajt ML, Jaeschke H, Bailey SM. Mitochondrial Protein Thiol Modifications in Acetaminophen Hepatotoxicity: effect on HMG-CoA Synthase. Toxicol Lett. 2008; 177(3):188-97.
Morgan RE, Trauner M, van Staden CJ, Lee PH, Ramachandran B, Eschenberg M, Afshari CA, Qualls CW Jr, Lightfoot-Dunn R, Hamadeh HK. Interference with bile salt export pump function is a susceptibility factor for human liver injury in drug development. Toxicol Sci. 2010;118(2):485-500.
Copple IM, Goldring CE, Jenkins RE, Chia AJ, Randle LE, Hayes JD, Kitteringham NR, Park BK. The hepatotoxic metabolite of acetaminophen directly activates the Keap1-Nrf2 cell defense system. Hepatology. 2008;48(4):1292-301.
Niture SK, Kaspar JW, Shen J, Jaiswal AK. Nrf2 signaling and cell survival. Toxicol Appl Pharmacol. 2010;244(1):37-42.
Pari L, Murugavel P. Protective effect of alpha-lipoic acid against chloroquine-induced hepatotoxicity in rats. J Appl Toxicol. 2004;24(1):21-6.
Mansour DF, El-Denshary ES, Bahgat AK, Nada SA. Hepatoprotective Effect of Alpha Lipoic Acid Against Bromobenzene-Induced Liver Damage in Rats. Med J Cairo Univ. 2009;77(4):23-30.
Çakır T, Baştürk A, Polat C, Aslaner A, Durgut H, Şehirli AÖ, Gül M, Öğünç AV, Gül S, Sabuncuoglu MZ, Oruç MT. Does alfa lipoic acid prevent liver from methotrexate induced oxidative injury in rats? Acta Cir Bras. 2015;30(4):247-52.
Slepneva IA, Sergeeva SV, Khramtsov VV. Reversible inhibition of NADPH-cytochrome
P450 reductase by alpha-lipoic acid. Biochem Biophys Res Commun. 1995;214(3):1246-53.
Ali SO, Darwish HA, Ismail NA. Modulatory effects of curcumin, silybin-phytosome and alpha-R-lipoic acid against thioacetamide-induced liver cirrhosis in rats. Chem Biol Interact. 2014;216:26-33.
Uskoković A, Dinić S, Arambašić Jovanović J, Poznanović G, Vidaković M, Mihailović M. Liver Diseases: Epigenetic Mechanisms, Oxidative stress and Use of Alpha-Lipoic Acid. In: Patel V, Preedy V, editors. The Handbook of Nutrition, Diet and Epigenetics. Springer International Publishing; 2017. p. 1-21.
Ichai P, Samuel D. Etiology and prognosis of fulminant hepatitis in adults. Liver Transpl. 2008;14:S67-S79.
Manzo-Avalos S, Saavedra-Molina A. Cellular and Mitochondrial Effects of Alcohol Consumption. Int J Environ Res Public Health. 2010;7(12):4281-304.
Li Y, Ma QG, Zhao LH, Guo YQ, Duan GX, Zhang JY, Ji C. Protective Efficacy of Alpha-lipoic Acid against AflatoxinB1-induced Oxidative Damage in the Liver. Asian-Australas J Anim Sci. 2014; 27(6):907-15.
Heibashy MIA, Mazen GMA, Shahin MI. The Curative Effects of some Antioxidants on Endotoxin Induced with Lipopolysaccharide in the Liver of Rats. J Am Sci. 2013;9(12):529-38.
El-Feki MA, Amin HM, Abdalla AA, Fesal M. Immunomodulatory and Anti- oxidant Effects of Alpha-Lipoic Acid and Vitamin E on Lipopolysaccharide-induced Liver Injury in Rats. Middle East J Appl Sci. 2016;06(03):460-7.