A patient-based iPSC-derived hepatocyte model of alcohol-associated cirrhosis reveals bioenergetic insights into disease pathogenesis

Bani Mukhopadhyay, Cheryl Marietta, Pei-Hong Shen, Abdul Oiseni, Faridoddin Mirshahi, Maria Mazzu, Colin Hodgkinson, Eli Winkler, Qiaoping Yuan, Daniel Miranda, George Kunos, Arun J. Sanyal and David Goldman ()
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Bani Mukhopadhyay: National Institute on Alcohol Abuse and Alcoholism, NIH
Cheryl Marietta: National Institute on Alcohol Abuse and Alcoholism, NIH
Pei-Hong Shen: National Institute on Alcohol Abuse and Alcoholism, NIH
Abdul Oiseni: Virginia Commonwealth University School of Medicine
Faridoddin Mirshahi: Virginia Commonwealth University School of Medicine
Maria Mazzu: National Institute on Alcohol Abuse and Alcoholism, NIH
Colin Hodgkinson: National Institute on Alcohol Abuse and Alcoholism, NIH
Eli Winkler: National Institute on Alcohol Abuse and Alcoholism, NIH
Qiaoping Yuan: National Institute on Alcohol Abuse and Alcoholism, NIH
Daniel Miranda: Inc
George Kunos: National Institute on Alcohol Abuse and Alcoholism, NIH
Arun J. Sanyal: Virginia Commonwealth University School of Medicine
David Goldman: National Institute on Alcohol Abuse and Alcoholism, NIH

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract Only ~20% of heavy drinkers develop alcohol cirrhosis (AC). While differences in metabolism, inflammation, signaling, microbiome signatures and genetic variations have been tied to the pathogenesis of AC, the key underlying mechanisms for this interindividual variability, remain to be fully elucidated. Induced pluripotent stem cell-derived hepatocytes (iHLCs) from patients with AC and healthy controls differ transcriptomically, bioenergetically and histologically. They include a greater number of lipid droplets (LDs) and LD-associated mitochondria compared to control cells. These pre-pathologic indicators are effectively reversed by Aramchol, an inhibitor of stearoyl-CoA desaturase. Bioenergetically, AC iHLCs have lower spare capacity, slower ATP production and their mitochondrial fuel flexibility towards fatty acids and glutamate is weakened. MARC1 and PNPLA3, genes implicated by GWAS in alcohol cirrhosis, show to correlate with lipid droplet-associated and mitochondria-mediated oxidative damage in AC iHLCs. Knockdown of PNPLA3 expression exacerbates mitochondrial deficits and leads to lipid droplets alterations. These findings suggest that differences in mitochondrial bioenergetics and lipid droplet formation are intrinsic to AC hepatocytes and can play a role in its pathogenesis.

Date: 2024
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DOI: 10.1038/s41467-024-47085-y

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