Drinking and Obesity: Alcoholic Liver Disease/Nonalcoholic Fatty Liver Disease Interactions

Åberg, Fredrik; Färkkilä, Martti

doi:10.1055/s-0040-1701443

Cited by 60 publications

(63 citation statements)

References 100 publications

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“…Additionally, we provide evidence that the concentration of circulating components of the necroptotic signaling network, RIP1 and RIP3, may provide important insight into the development of biomarkers to distinguish AH from NASH. Such biomarkers are becoming increasingly important as many patients presenting with symptoms of metabolic liver disease are both obese and chronic heavy drinkers (33). In our study, the circulating concentrations of RIP1 and RIP3 were different in patients with AH compared with NASH, even when AH patients were stratified by disease severity.…”

Section: Discussionmentioning

confidence: 64%

Differential role of MLKL in alcohol-associated and non–alcohol-associated fatty liver diseases in mice and humans

Miyata¹,

Wu²,

Fan³

et al. 2021

JCI Insight

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Hepatocellular death contributes to progression of alcohol–associated (ALD-associated) and non–alcohol-associated (NAFL/NASH) liver diseases. However, receptor-interaction protein kinase 3 (RIP3), an intermediate in necroptotic cell death, contributes to injury in murine models of ALD but not NAFL/NASH. We show here that a differential role for mixed-lineage kinase domain–like protein (MLKL), the downstream effector of RIP3, in murine models of ALD versus NAFL/NASH and that RIP1-RIP3-MLKL can be used as biomarkers to distinguish alcohol-associated hepatitis (AH) from NASH. Phospho-MLKL was higher in livers of patients with NASH compared with AH or healthy controls (HCs). MLKL expression, phosphorylation, oligomerization, and translocation to plasma membrane were induced in WT mice fed diets high in fat, fructose, and cholesterol but not in response to Gao-binge (acute on chronic) ethanol exposure. Mlkl –/– mice were not protected from ethanol-induced hepatocellular injury, which was associated with increased expression of chemokines and neutrophil recruitment. Circulating concentrations of RIP1 and RIP3, but not MLKL, distinguished patients with AH from HCs or patients with NASH. Taken together, these data indicate that MLKL is differentially activated in ALD/AH compared with NAFL/NASH in both murine models and patients. Furthermore, plasma RIP1 and RIP3 may be promising biomarkers for distinguishing AH and NASH.

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Section: Discussionmentioning

confidence: 64%

Differential role of MLKL in alcohol-associated and non–alcohol-associated fatty liver diseases in mice and humans

Miyata¹,

Wu²,

Fan³

et al. 2021

JCI Insight

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“…In addition, underreporting of alcohol use is a major concern, particularly when assessing patients who are aware of their liver disease. ( 49,50 )…”

Section: Discussionmentioning

confidence: 99%

An Experimental DUAL Model of Advanced Liver Damage

et al. 2021

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Individuals exhibiting an intermediate alcohol drinking pattern in conjunction with signs of metabolic risk present clinical features of both alcohol-associated and metabolic-associated fatty liver diseases. However, such combination remains an unexplored area of great interest, given the increasing number of patients affected. In the present study, we aimed to develop a preclinical DUAL (alcohol-associated liver disease plus metabolic-associated fatty liver disease) model in mice. C57BL/6 mice received 10% vol/vol alcohol in sweetened drinking water in combination with a Western diet for 10, 23, and 52 weeks (DUAL model). Animals fed with DUAL diet elicited a significant increase in body mass index accompanied by a pronounced hypertrophy of adipocytes, hypercholesterolemia, and hyperglycemia. Significant liver damage was characterized by elevated plasma alanine aminotransferase and lactate dehydrogenase levels, extensive hepatomegaly, hepatocyte enlargement, ballooning, steatosis, hepatic cell death, and compensatory proliferation. Notably, DUAL animals developed lobular inflammation and advanced hepatic fibrosis. Sequentially, bridging cirrhotic changes were frequently observed after 12 months. Bulk RNA-sequencing analysis indicated that dysregulated molecular pathways in DUAL mice were similar to those of patients with steatohepatitis. Conclusion: Our DUAL model is characterized by obesity, glucose intolerance, liver damage, prominent steatohepatitis and fibrosis, as well as inflammation and fibrosis in white adipose tissue. Altogether, the DUAL model mimics all histological, metabolic, and transcriptomic gene signatures of human advanced steatohepatitis, and therefore serves as a preclinical tool for the development of therapeutic targets. (Hepatology Communications 2021;0:1-18). Excessive alcohol drinking is a leading cause of chronic liver disease and accounts for up to 60%-80% of liver-related mortality in Europe. (1) These data become even more relevant considering that alcohol-associated liver disease (ALD) receives only about 5% of the attention in the field of hepatology. (2) The principal fact that only about 6%-30% of heavy drinkers develop cirrhosis indicates that additional factors modulate the risk of ALD progression. (1) Clinical observations commonly suggest a wide individual susceptibility, and indicate several risk factors for ALD including drinking patterns, female gender, genetic background, cigarette smoking, occupational hazards, and hepatotropic viruses. Obesity and metabolic syndrome (MS) represent another important group of risk factors that accelerate fibrosis

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“…When assessing the overall impact of NAFLD on clinical liver outcomes in the general population, there is a need to recognize that NAFLD often co-exists with alcohol-related liver disease, and that metabolic risk factors and alcohol use have bi-directional interaction effects on liver disease with in general higher risk for liver-related outcomes in persons with mixed etiologies (28,29). In such research settings, the exclusion of competing and co-existent causes for liver disease may lead to lower risk estimates associated with NAFLD.…”

Section: Accepted Articlementioning

confidence: 99%

Administrative Coding in Electronic Health Care Record‐Based Research of NAFLD: An Expert Panel Consensus Statement

Hagström

Adams

Allen³

et al. 2021

Hepatology

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151

131

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Drinking and Obesity: Alcoholic Liver Disease/Nonalcoholic Fatty Liver Disease Interactions

Cited by 60 publications

References 100 publications

Differential role of MLKL in alcohol-associated and non–alcohol-associated fatty liver diseases in mice and humans

Differential role of MLKL in alcohol-associated and non–alcohol-associated fatty liver diseases in mice and humans

An Experimental DUAL Model of Advanced Liver Damage

Administrative Coding in Electronic Health Care Record‐Based Research of NAFLD: An Expert Panel Consensus Statement

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