Emerging Metabolic and Transcriptomic Signature of PNPLA3-Associated NASH.
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ABSTRACT:
SUBMITTER: Dhar D
PROVIDER: S-EPMC9683537 | biostudies-literature | 2021 Apr
REPOSITORIES: biostudies-literature
Publications
Emerging Metabolic and Transcriptomic Signature of PNPLA3-Associated NASH.
Dhar Debanjan D Loomba Rohit R
Hepatology (Baltimore, Md.) 20210401 4
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Project description:Background and aimsThe genetic PNPLA3 polymorphism I148M has been extensively associated with higher risk for development and progression of NAFLD towards NASH.MethodsPNPLA3 and α-SMA expression were quantified in liver biopsies collected from NASH patients (n = 26) with different fibrosis stages and PNPLA3 genotypes. To study the potential mechanisms driving PNPLA3 expression during NASH progression towards fibrosis, hepatocytes and hepatic stellate cells (HSCs) were cultivated in low and high glucose medium. Moreover, hepatocytes were treated with increasing concentrations of palmitic acid alone or in combination with glucose. Conditioned media were collected from challenged hepatocytes to stimulate HSCs.ResultsTissue expression of PNPLA3 was significantly enhanced in biopsies of patients carrying the I148M polymorphism compared to wild type (WT). In NASH biopsies, PNPLA3 significantly correlated with fibrosis stage and α-SMA levels independently of PNPLA3 genotype. In line, PNPLA3 expression was higher in α-SMA positive cells. Low glucose increased PNPLA3 in HSCs, whereas high glucose induced PNPLA3 and de-novo lipogenesis-related genes expression in hepatocytes. Palmitic acid induced fat accumulation and cell stress markers in hepatocytes, which could be counteracted by oleic acid. Conditioned media collected from lipotoxic challenged hepatocytes markedly induced PNPLA3 mRNA and protein levels, fibrogenic and autophagic markers and promoted migration in HSCs. Notably, conditioned media collected from hepatocytes cultivated with both glucose and palmitic acid exacerbated HSCs migration, PNPLA3 and fibrogenic gene expression, promoting release of cytokines from HSCs.ConclusionsCollectively, our observations uncover the diverse metabolic regulation of PNPLA3 among different hepatic cell populations and support its relation to fibrosis progression.
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Project description:Genotype-phenotype associations for common diseases are often compounded by pleiotropy and metabolic state. Here, we devised a pooled human organoid-panel of steatohepatitis to investigate the impact of metabolic status on genotype-phenotype association. En masse population-based phenotypic analysis under insulin insensitive conditions predicted key non-alcoholic steatohepatitis (NASH)-genetic factors including the glucokinase regulatory protein (GCKR)-rs1260326:C>T. Analysis of NASH clinical cohorts revealed that GCKR-rs1260326-T allele elevates disease severity only under diabetic state but protects from fibrosis under non-diabetic states. Transcriptomic, metabolomic, and pharmacological analyses indicate significant mitochondrial dysfunction incurred by GCKR-rs1260326, which was not reversed with metformin. Uncoupling oxidative mechanisms mitigated mitochondrial dysfunction and permitted adaptation to increased fatty acid supply while protecting against oxidant stress, forming a basis for future therapeutic approaches for diabetic NASH. Thus, "in-a-dish" genotype-phenotype association strategies disentangle the opposing roles of metabolic-associated gene variant functions and offer a rich mechanistic, diagnostic, and therapeutic inference toolbox toward precision hepatology. VIDEO ABSTRACT.
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