Pathogenesis of Alcohol-Associated Liver Disease

Exposure to hepatotoxic chemicals is involved in liver disease-related morbidity and mortality worldwide. The liver responds to damage by triggering compensatory hepatic regeneration. Physical agent or chemical-induced liver damage disrupts hepatocyte proteostasis, including endoplasmic reticulum (ER) homeostasis. Post liver injury ER experiences a homeostatic imbalance, followed by active ER stress response signaling. Activated ER stress response causes selective upregulation of stress response genes and downregulation of many hepatocyte genes. Acetaminophen overdose, CCl4, acute and chronic alcohol exposure, and physical injury activates the ER stress response, but details about the cellular consequences of the ER stress response on liver regeneration remain unclear. The current data indicate that inhibiting the ER stress response after partial hepatectomy-induced liver damage promotes liver regeneration, whereas inhibiting the ER stress response after chemical-induced hepatotoxicity impairs liver regeneration. This review summarizes key findings and emphasizes the knowledge gaps in role of ER stress in injury and regeneration.

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“…Continued consumption of alcohol can lead to liver fibrosis which can progress to liver cirrhosis and hepatocellular carcinoma (HCC). 97…”

Section: The Role Of Er Stress During Liver Pathogenesis and Regenera...mentioning

confidence: 99%

The Role of Endoplasmic Reticulum Stress Response in Liver Regeneration

Deshmukh

Apte

2023

Semin Liver Dis

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“…Thus, there remains a critical need to identify additional mechanisms responsible for liver fibrosis from which novel therapeutic strategies can be developed. This is especially pertinent today given the increased need for donor organs due to the burgeoning obesity epidemic, a staggering increase in alcohol consumption and severe ALD associated with the COVID‐19 pandemic, and increasing ALD in women (Kezer et al, 2021; Osna et al, 2022). One area that lags behind several others is an understanding of how the ECM and its multitude of bioactive fragments contribute to fibrogenesis and fibrosis progression.…”

Section: Introductionmentioning

confidence: 99%

“…Alcohol-associated liver disease (ALD) consists of a spectrum of hepatic pathologies ranging from simple steatosis through cirrhosis and hepatocellular carcinoma (Gao & Bataller, 2011;Osna et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

Hyaluronan synthesis inhibition normalizes ethanol‐enhanced hepatic stellate cell activation

Kotulkar

Robarts

Lin‐Rahardja

et al. 2023

Alcohol: Clinical and Experimental Research

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BackgroundChronic ethanol overconsumption promotes alcohol‐associated liver disease (ALD), characterized by hepatocyte injury, inflammation, hepatic stellate cell (HSC) activation, and fibrosis. Hyaluronan (HA) concentration is greater in livers and blood from advanced ALD patients than patients with advanced non‐ALD. In the liver, HSCs are the major HA producers. The relationship between ethanol, HA, and HSC activation is incompletely understood. Thus, here, we tested the hypothesis that ethanol enhances HSC activation in a HA‐dependent manner.MethodsLiver tissue microarrays (TMAs) containing steatotic livers from donors with or without a history of alcohol consumption were used to measure HA and collagen content. Mice were fed a moderate (2%, v/v) ethanol‐containing diet or pair‐fed control diet for 2 days, after which they were given a single carbon tetrachloride (CCl4) injection. To inhibit HA synthesis, we provided 4‐methylumbelliferone (4MU) daily. We used LX2 cells, a human HSC cell line, to determine the impact ethanol had on LPS responses, with or without concurrent 4MU exposure.ResultsCCl4 induced liver injury, but it did not differ between ethanol or control diet fed mice with or without 4MU treatment. Ethanol feeding enhanced CCl4‐induced hepatic HA content, which was paralleled by HA synthase (Has)2 transcript abundance; 4MU treatment normalized both. Consistently, HSC activation, assessed by measuring αSMA mRNA and protein, was induced by CCl4 exposure, enhanced by ethanol feeding, and normalized by 4MU. Hepatic transcripts, but not protein, for Ccl2 were enhanced by ethanol feeding and normalized by 4MU exposure. Finally, ethanol‐exposed LX2 cells made more LPS‐stimulated CCL2 mRNA and protein than cells not exposed to ethanol; 4MU prevented this.ConclusionThese data show that ethanol augments HSC activation through HA synthesis and enhances hepatic profibrogenic features. Therefore, targeting HSC HA production could potentially attenuate liver disease in ALD patients.

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“…Patients have also been found to express fibrosis in the liver, which has been found to end in late‐state cirrhosis in the liver. [ 12 ]…”

Section: Introductionmentioning

confidence: 99%

“…Patients have also been found to express fibrosis in the liver, which has been found to end in late-state cirrhosis in the liver. [12] NAFLD (nonalcoholic fatty liver disease) is defined as hepatic steatosis conditions without a substantial alcohol intake. Though there is a hereditary component to the susceptibility of NAFLD, elevating insulin resistance is closely connected to the disease's start and progression.…”

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confidence: 99%

Molecular mechanisms of alcohol's effects on the human body: A review and update

Renu,

Myakala,

Chakraborty

et al. 2023

J Biochem & Molecular Tox

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Alcohol consumption has been linked to numerous negative health outcomes although it has some beneficial effects on moderate dosages, the most severe of which being alcohol‐induced hepatitis. The number of people dying from this liver illness has been shown to climb steadily over time, and its prevalence has been increasing. Researchers have found that alcohol consumption primarily affects the brain, leading to a wide range of neurological and psychological diseases. High‐alcohol‐consumption addicts not only experienced seizures, but also ataxia, aggression, social anxiety, and variceal hemorrhage that ultimately resulted in death, ascites, and schizophrenia. Drugs treating this liver condition are limited and can cause serious side effects like depression. Serine‐threonine kinases, cAMP protein kinases, protein kinase C, ERK, RACK 1, Homer 2, and more have all been observed to have their signaling pathways disrupted by alcohol, and alcohol has also been linked to epigenetic changes. In addition, alcohol consumption induces dysbiosis by changing the composition of the microbiome found in the gastrointestinal tract. Although more studies are needed, those that have been done suggest that probiotics aid in keeping the various microbiota concentrations stable. It has been argued that reducing one's alcohol intake may seem less harmful because excessive drinking is a lifestyle disorder.

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Pathogenesis of Alcohol-Associated Liver Disease

Cited by 37 publications

References 287 publications

The Role of Endoplasmic Reticulum Stress Response in Liver Regeneration

The Role of Endoplasmic Reticulum Stress Response in Liver Regeneration

Hyaluronan synthesis inhibition normalizes ethanol‐enhanced hepatic stellate cell activation

Molecular mechanisms of alcohol's effects on the human body: A review and update

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