The PNPLA3 I148M variant modulates the fibrogenic phenotype of human hepatic stellate cells

Bruschi, Francesca Virginia; Claudel, Thierry; Tardelli, Matteo; Caligiuri, Alessandra; Stulnig, Thomas M.; Marra, Fabio; Trauner, Michael

doi:10.1002/hep.29041

Cited by 191 publications

(226 citation statements)

References 36 publications

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“…Enzymes involved in retinol metabolism are up‐regulated in hepatic lipid droplets in NAFLD . Furthermore, PNPLA3, strongly associated with NAFLD, acts as a retinyl‐palmitate lipase to control serum retinol and the RBP4 level in NAFLD patients and to modulate stellate cell fibrogenesis . This supports the critical role retinoid metabolism plays in NAFLD progression.…”

Section: Discussionmentioning

confidence: 60%

17‐Beta Hydroxysteroid Dehydrogenase 13 Is a Hepatic Retinol Dehydrogenase Associated With Histological Features of Nonalcoholic Fatty Liver Disease

et al. 2019

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Nonalcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease. A single‐nucleotide polymorphism (SNP), rs6834314, was associated with serum liver enzymes in the general population, presumably reflecting liver fat or injury. We studied rs6834314 and its nearest gene, 17‐beta hydroxysteroid dehydrogenase 13 (HSD17B13), to identify associations with histological features of NAFLD and to characterize the functional role of HSD17B13 in NAFLD pathogenesis. The minor allele of rs6834314 was significantly associated with increased steatosis but decreased inflammation, ballooning, Mallory‐Denk bodies, and liver enzyme levels in 768 adult Caucasians with biopsy‐proven NAFLD and with cirrhosis in the general population. We found two plausible causative variants in the HSD17B13 gene. rs72613567, a splice‐site SNP in high linkage with rs6834314 (r2 = 0.94) generates splice variants and shows a similar pattern of association with NAFLD histology. Its minor allele generates simultaneous expression of exon 6‐skipping and G‐nucleotide insertion variants. Another SNP, rs62305723 (encoding a P260S mutation), is significantly associated with decreased ballooning and inflammation. Hepatic expression of HSD17B13 is 5.9‐fold higher (P = 0.003) in patients with NAFLD. HSD17B13 is targeted to lipid droplets, requiring the conserved amino acid 22‐28 sequence and amino acid 71‐106 region. The protein has retinol dehydrogenase (RDH) activity, with enzymatic activity dependent on lipid droplet targeting and cofactor binding site. The exon 6 deletion, G insertion, and naturally occurring P260S mutation all confer loss of enzymatic activity. Conclusion: We demonstrate the association of variants in HSD17B13 with specific features of NAFLD histology and identify the enzyme as a lipid droplet–associated RDH; our data suggest that HSD17B13 plays a role in NAFLD through its enzymatic activity.

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Section: Discussionmentioning

confidence: 60%

17‐Beta Hydroxysteroid Dehydrogenase 13 Is a Hepatic Retinol Dehydrogenase Associated With Histological Features of Nonalcoholic Fatty Liver Disease

et al. 2019

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“…Underlying mechanisms explaining HSC activation in aging revealed no modification in different proinflammatory mediators including TLR4, NFκB, and TGFβ (data not shown), but interestingly suggested alterations in retinoid metabolism and breakdown. In fact, aged livers exhibited down‐regulated CRBP‐1 together with over‐expressed PNPLA3, which have been associated with HSC activation and susceptibility to develop steatohepatitis (Bruschi et al, 2017; Uchio et al, 2002). …”

Section: Discussionmentioning

confidence: 99%

Effects of aging on liver microcirculatory function and sinusoidal phenotype

et al. 2018

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The socioeconomic and medical improvements of the last decades have led to a relevant increase in the median age of worldwide population. Although numerous studies described the impact of aging in different organs and the systemic vasculature, relatively little is known about liver function and hepatic microcirculatory status in the elderly. In this study, we aimed at characterizing the phenotype of the aged liver in a rat model of healthy aging, particularly focusing on the microcirculatory function and the molecular status of each hepatic cell type in the sinusoid. Moreover, major findings of the study were validated in young and aged human livers. Our results demonstrate that healthy aging is associated with hepatic and sinusoidal dysfunction, with elevated hepatic vascular resistance and increased portal pressure. Underlying mechanisms of such hemodynamic disturbances included typical molecular changes in the cells of the hepatic sinusoid and deterioration in hepatocyte function. In a specific manner, liver sinusoidal endothelial cells presented a dysfunctional phenotype with diminished vasodilators synthesis, hepatic macrophages exhibited a proinflammatory state, while hepatic stellate cells spontaneously displayed an activated profile. In an important way, major changes in sinusoidal markers were confirmed in livers from aged humans. In conclusion, our study demonstrates for the first time that aging is accompanied by significant liver sinusoidal deregulation suggesting enhanced sinusoidal vulnerability to chronic or acute injuries.

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“…Patatin like phospholipase domain containing 3 (PNPLA3) is highly expressed in HSCs and hepatocytes, and hydrolyzes retinol palmitate to retinol and palmitic acid with influence from retinol availability, and its over-expression is associated with reduced cytoplasmic lipid droplets. A single nucleotide polymorphism (SNP) in the PNPLA3 gene, I148M, is associated with its reduced expression, more advanced NAFLD fibrosis, and HCC, and may have functional implication in HSC activation [305]. …”

Section: Mechanisms Of Hsc Activationmentioning

confidence: 99%

Hepatic stellate cells as key target in liver fibrosis

Higashi

Friedman

Hoshida

2017

Advanced Drug Delivery Reviews

1,036

894

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Progressive liver fibrosis, induced by chronic viral and metabolic disorders, leads to more than one million deaths annually via development of cirrhosis, although no antifibrotic therapy has been approved to date. Transdifferentiation (or “activation”) of hepatic stellate cells is the major cellular source of matrix protein-secreting myofibroblasts, the major driver of liver fibrogenesis. Paracrine signals from injured epithelial cells, fibrotic tissue microenvironment, immune and systemic metabolic dysregulation, enteric dysbiosis, and hepatitis viral products can directly or indirectly induce stellate cell activation. Dysregulated intracellular signaling, epigenetic changes, and cellular stress response represent candidate targets to deactivate stellate cells by inducing reversion to inactivated state, cellular senescence, apoptosis, and/or clearance by immune cells. Cell type- and target-specific pharmacological intervention to therapeutically induce the deactivation will enable more effective and less toxic precision antifibrotic therapies.

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The PNPLA3 I148M variant modulates the fibrogenic phenotype of human hepatic stellate cells

Cited by 191 publications

References 36 publications

17‐Beta Hydroxysteroid Dehydrogenase 13 Is a Hepatic Retinol Dehydrogenase Associated With Histological Features of Nonalcoholic Fatty Liver Disease

17‐Beta Hydroxysteroid Dehydrogenase 13 Is a Hepatic Retinol Dehydrogenase Associated With Histological Features of Nonalcoholic Fatty Liver Disease

Effects of aging on liver microcirculatory function and sinusoidal phenotype

Hepatic stellate cells as key target in liver fibrosis

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