Review
Version 1
Preserved in Portico This version is not peer-reviewed
Pathogenesis of Alcoholic Fatty Liver a Narrative Review
Version 1
: Received: 8 May 2023 / Approved: 9 May 2023 / Online: 9 May 2023 (08:38:13 CEST)
A peer-reviewed article of this Preprint also exists.
Seitz, H.K.; Moreira, B.; Neuman, M.G. Pathogenesis of Alcoholic Fatty Liver a Narrative Review. Life 2023, 13, 1662. Seitz, H.K.; Moreira, B.; Neuman, M.G. Pathogenesis of Alcoholic Fatty Liver a Narrative Review. Life 2023, 13, 1662.
Abstract
Alcohol effects on hepatic lipid metabolism through various mechanisms, leading synergistically to an accumulation of fatty acids (FA) and triglycerides. Obesity, as well as, the dietary fat [saturated fatty acids (FA) versus poly-unsaturated fatty acids (PUFA)] may modulate the hepatic fat. Alcohol inhibits adenosine monophosphate activated kinase (AMPK). AMPK activates peroxisome proliferators activated receptor a (PPARα) and leads to a decreased activation of sterol regulatory element binding protein 1c (SRABP1c).
The inhibition of AMPK, and thus of PPARα results in an inhibition of FAs oxidation. This ß-oxidation is further reduced due to mitochondrial damage induced through cytochrome P4502E1 (CYP2E1) driven oxidative stress. Furthermore, the synthesis of FAs is stimulated through an activation of SHREP1. In addition, alcohol consumption leads to a reduced production of adiponectin in adipocytes due to oxidative stress and to an increased mobilization of FAs from adipose tissue and from the gut as chylomicrons.
On the other side, the secretion of FAs via very low density lipoproteins (VLDL) from the liver is inhibited by alcohol. Alcohol also affects signal pathways such as early growth response 1 (Egr-1) associated with the expression of tumour necrosis factor (TNF), and the mammalian target of rapamycin (mTOR) a key regulator of autophagy. Both have influence the pathogenesis of alcoholic fatty liver.
Alcohol-induced gut dysbiosis is contributing to the severity of ALD by increasing metabolism of ethanol in the gut and promoting intestinal dysfunction. Moreover, pathogen associated molecular paterns (PAMPS) via specific Toll-like receptors (TLR) bacterial overgrowth is leading to the translocation of bacteria. Endotoxins, and toxic ethanol metabolites enter the enterohepatic circulation reaching the liver, inducing the activation of the nuclear factor kappa-B (NFB) pathway.
Pro-inflammatory cytokines released in the process contribute to inflammation and fibrosis. In addition, cellular apoptosis is inhibited in the favor of necrosis.
Keywords
alcoholic fatty liver; adenosine monophosphate activated kinase; sterol regulatory element binding protein 1c; peroxisome proliferator activated receptor , oxidative stress; cytochrome P450 2E1
Subject
Medicine and Pharmacology, Anatomy and Physiology
Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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