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Review
. 2023 May 4;21(1):300.
doi: 10.1186/s12967-023-04166-8.

Pathogenic mechanisms and regulatory factors involved in alcoholic liver disease

Chuyun Yan  1 , Wanting Hu  2 , Jinqi Tu  3 , Jinyao Li  4 , Qionglin Liang  2 , Shuxin Han  5   6
Affiliations
Review

Pathogenic mechanisms and regulatory factors involved in alcoholic liver disease

Chuyun Yan et al. J Transl Med. .

Abstract

Alcoholism is a widespread and damaging behaviour of people throughout the world. Long-term alcohol consumption has resulted in alcoholic liver disease (ALD) being the leading cause of chronic liver disease. Many metabolic enzymes, including alcohol dehydrogenases such as ADH, CYP2E1, and CATacetaldehyde dehydrogenases ALDHsand nonoxidative metabolizing enzymes such as SULT, UGT, and FAEES, are involved in the metabolism of ethanol, the main component in alcoholic beverages. Ethanol consumption changes the functional or expression profiles of various regulatory factors, such as kinases, transcription factors, and microRNAs. Therefore, the underlying mechanisms of ALD are complex, involving inflammation, mitochondrial damage, endoplasmic reticulum stress, nitrification, and oxidative stress. Moreover, recent evidence has demonstrated that the gut-liver axis plays a critical role in ALD pathogenesis. For example, ethanol damages the intestinal barrier, resulting in the release of endotoxins and alterations in intestinal flora content and bile acid metabolism. However, ALD therapies show low effectiveness. Therefore, this review summarizes ethanol metabolism pathways and highly influential pathogenic mechanisms and regulatory factors involved in ALD pathology with the aim of new therapeutic insights.

Keywords: Alcoholic liver disease; Metabolic enzymes; Pathogenic mechanisms; Regulatory factors; Therapeutic implications.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
The absorption, transportation, and deposition of alcohol in the body. After oral ingestion, most alcohol is absorbed in the stomach (~ 22%) or the intestine (~ 75%), with only a small part deposited in faeces (1%) or absorbed in the oesophagus. The absorbed alcohol is transported mainly through the blood circulatory system to the liver where it is metabolized (~ 95%), with only a small portion excreted in urine (~ 2%-4%) or as an exhaled gas (~ 5%) in its original form
Fig. 2
Fig. 2
Ethanol metabolism pathways in the liver. In hepatocytes, three main oxidative pathways metabolize ethanol. Ethanol is metabolized to acetaldehyde by ADHs, CYP2E1, and catalase. Acetaldehyde is further metabolized into acetic acid by ALDHs. Acetic acid is then converted into acetyl-CoA by acetyl-CoA synthase, after which it enters the tricarboxylic acid cycle. Moreover, ethanol can be alternatively metabolized into the nonoxidative metabolites EtS, EtG, Peth, and FAEEs via the action of SULT, UGT, FAEES, AEAT, and PLD. EtS and EtG are water-soluble metabolites that are mainly excreted in the urine. ADH Alcohol dehydrogenases; EtS Ethyl sulfate; EtG Ethyl glucuronide; PEth Phosphatidylethanolfaees, fatty acid ethyl esters; SULT Sulfotransferase; UGT Glucuronosyltransferase; FAEES FAEE synthase; AEAT Acyl-CoA: ethanol O-acyltransferase; PLD Phospholipase ; DCAT Catalase; ALDH Aldehyde dehydrogenase; OAA Oxaloacetate
Fig. 3
Fig. 3
Mechanisms of ethanol-induced liver injury. Ethanol can upregulate lipid synthase and FA transporter activity to increase lipid synthesis and downregulate lipid transporters and β-oxidases to reduce lipid consumption, which eventually leads to lipid accumulation. ROS produced by ethanol oxidative metabolism triggers the release of proinflammatory cytokines and activates a variety of immune cells to release chemokines and cytokines, leading to immuno-inflammatory responses. Ethanol also inhibits tight junctions to disrupt the intestinal barrier, inducing intestinal LPS translocation to further stimulate the inflammatory response in the liver. In hepatocytes, ROS and lipid peroxidation products generated during ethanol metabolism activate oxidative stress and ER stress reactions in multiple organ systems. ACE and FAEEs, metabolites of ethanol, also induce mitochondrial dysfunction. ROS, reactive oxidative species; LPS lipopolysaccharide; FAs fatty acids; ER stress Endoplasmic reticulum stress; ACE acetaldehyde; FAEEs Fatty acid ethyl esters
Fig. 4
Fig. 4
Regulatory factors in ALD. Ethanol is absorbed by villous epithelial cells in the intestine and is mostly transported to the liver for metabolism. Ethanol downregulates AMPK, SIRT1, miR-122, and FXR activity, increases the expression of lipid synthesis genes, and inhibits PPARα-mediated β-oxidation of fatty acids (FAs), leading to ethanol-induced fat accumulation in hepatocytes. The upregulation of miR-155 but suppression of AMPK initiated by ethanol activates apoptosis pathways in the liver. Increased bile acid synthesis due to ethanol-induced inhibition of FXR also accelerates hepatic apoptosis. The upregulation of NF-κB by ethanol stimulates the release of inflammatory factors and chemokines, leading to alcoholic hepatitis (AH). The body develops defences against the toxic effects of ethanol. For example, NRF2 is induced in hepatocytes by ethanol and promotes adaptive resistance to ethanol-initiated oxidative stress. SIRT1 sirtuin 1miR-122, microRNA-122FXRPPARαmiR-155, microRNA-155AMPK, AMP-activated protein kinaseNF-κB, nuclear factor-kappaBNRF2, nuclear factor E2-related factor 2
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