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Liver Diseases: Epigenetic Mechanisms, Oxidative Stress and Use of Alpha-Lipoic Acid

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Abstract

The liver is the central organ for lipid and glucose metabolism. Impaired homeostasis of metabolism promotes the development of nonalcoholic fatty liver disease which is recognized worldwide as the most common liver disease. It covers the entire spectrum of liver disorders, from steatosis which can progress to steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Nonalcoholic fatty liver disease is primarily associated with the metabolic syndrome, which is assumed to represent the hepatic manifestation of the metabolic syndrome. Besides endogenous factors such as the metabolic syndrome, obesity, hypertriglyceridemia, and diabetes, all important risk factors for the development and progression of liver injury, increased alcohol consumption, certain drugs, and environmental contaminants can also induce hepatotoxicity. Epigenetic alterations that are involved in the regulation of hepatic lipid metabolism and the oxidative stress response are important players in the development and progression of liver diseases. Concerning the vital role of oxidative stress in the etiology of liver injury, a number of studies have established the efficacy of antioxidants in the prevention and treatment of liver disease. Alpha-lipoic acid is a naturally occurring compound with a powerful in vivo antioxidant activity that can modulate the redox status of cells and the activities of proteins, thus affecting cell signaling and transcriptional responses involved in glucose and lipid metabolism. This review summarizes the effects of alpha-lipoic acid in liver pathologies related to obesity, metabolic disorders, diabetes, nonalcoholic fatty liver disease, drug toxicity, and radiation. The many beneficial effects of alpha-lipoic acid include improvement of liver transaminases, enhanced scavenging of reactive oxygen species, increased activities of antioxidant enzymes and the resulting decrease in oxidative stress and inflammatory signals, reduced DNA damage, suppression of the fibrotic process, and improved lipid metabolism. In addition, alpha-lipoic acid administration could indirectly prevent epigenetic modifications in the liver by scavenging reactive oxygen species and regulating the NAD+/NADH ratio which is important for NAD+-dependent deacetylase sirtuin activity. Alpha-lipoic acid also mitigates the changes in DNA methylation in rat liver induced by low-density irradiation. However, the majority of alpha-lipoic acid actions have been primarily observed in in vitro and in vivo experimental studies. Translation of this biological knowledge and experimental data to human clinical use warrants further investigation.

Keywords

  • Nonalcoholic fatty liver disease
  • Steatosis
  • Fibrosis
  • Alpha-lipoic acid
  • Drug toxicity
  • Reactive oxygen species
  • Oxidative stress
  • Antioxidant enzymes
  • DNA methylation
  • Sirtuins

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Abbreviations

α-SMA:

α-smooth muscle actin

ALT:

Alanine aminotransferase

AMPK:

AMP-activated protein kinase

ARE:

Antioxidant response element

AST:

Aspartate aminotransferase

CAT:

Catalase

CBP:

CREB binding protein

DHLA:

Dihydrolipoic acid

FoxO:

Forkhead box O

Foxo3a:

Forkhead transcription factor 3a

GCL:

γ-Glutamylcysteine ligase

GCLC:

Catalytic subunit of GCL

GCLM:

Modulatory subunit of GCL

GPx:

Glutathione peroxidase

GSH:

Glutathione

GSSG:

Oxidized glutathione

HAT:

Histone acetyl transferases

HDAC:

Histone deacetylases

4HNE:

4-hydroxynonenal

HSC:

Hepatic stellate cells

LA:

Alpha-lipoic acid

miRNA:

microRNA

MDA:

Malondialdehyde

MMP-2:

Matrix metalloproteinase-2

NAFLD:

Nonalcoholic fatty liver disease

Nrf2:

Nuclear factor erythroid 2-related factor 2

ROS:

Reactive oxygen species

SAM:

S-adenosyl methionine

SIRT1:

Sirtuin 1

SOD:

Superoxide dismutase

SREBP-1:

Sterol regulatory element-binding protein 1

TGF-β1:

Transforming growth factor-β1.

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Acknowledgement

This work was supported by the Ministry of Education, Science and Technological Development of the Republic of Serbia, Grant No. 173020.

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Correspondence to Aleksandra Uskoković .

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Uskoković, A., Dinić, S., Jovanović, J.A., Poznanović, G., Vidaković, M., Mihailović, M. (2018). Liver Diseases: Epigenetic Mechanisms, Oxidative Stress and Use of Alpha-Lipoic Acid. In: Patel, V., Preedy, V. (eds) Handbook of Nutrition, Diet, and Epigenetics. Springer, Cham. https://doi.org/10.1007/978-3-319-31143-2_112-1

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  • DOI: https://doi.org/10.1007/978-3-319-31143-2_112-1

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