Dataset Information

Interaction between PNPLA3 I148M variant and age at infection in determining fibrosis progression in chronic hepatitis C.

ABSTRACT:

Background and aims

The PNPLA3 I148M sequence variant favors hepatic lipid accumulation and confers susceptibility to hepatic fibrosis and hepatocellular carcinoma. The aim of this study was to estimate the effect size of homozygosity for the PNPLA3 I148M variant (148M/M) on the fibrosis progression rate (FPR) and the interaction with age at infection in chronic hepatitis C (CHC).

Methods

FPR was estimated in a prospective cohort of 247 CHC patients without alcohol intake and diabetes, with careful estimation of age at infection and determination of fibrosis stage by Ishak score.

Results

Older age at infection was the strongest determinant of FPR (p<0.0001). PNPLA3 148M/M was associated with faster FPR in individuals infected at older age (above the median, 21 years; -0.64±0.2, n?=?8 vs. -0.95±0.3, n?=?166 log10 FPR respectively; p?=?0.001; confirmed for lower age thresholds, p<0.05), but not in those infected at younger age (p?=?ns). The negative impact of PNPLA3 148M/M on fibrosis progression was more marked in subjects at risk of altered hepatic lipid metabolism (those with grade 2-3 steatosis, genotype 3, and overweight; p<0.05). At multivariate analysis, PNPLA3 148M/M was associated with FPR (incremental effect 0.08±0.03 log10 fibrosis unit per year; p?=?0.022), independently of several confounders, and there was a significant interaction between 148M/M and older age at infection (p?=?0.025). The association between 148M/M and FPR remained significant even after adjustment for steatosis severity (p?=?0.032).

Conclusions

We observed an interaction between homozygosity for the PNPLA3 I148M variant and age at infection in determining fibrosis progression in CHC patients.

SUBMITTER: De Nicola S

PROVIDER: S-EPMC4149487 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Publications

Interaction between PNPLA3 I148M variant and age at infection in determining fibrosis progression in chronic hepatitis C.

De Nicola Stella S Dongiovanni Paola P Aghemo Alessio A Cheroni Cristina C D'Ambrosio Roberta R Pedrazzini Michele M Marabita Francesco F Donnici Lorena L Maggioni Marco M Fargion Silvia S Colombo Massimo M De Francesco Raffaele R Valenti Luca L

PloS one 20140829 8

<h4>Background and aims</h4>The PNPLA3 I148M sequence variant favors hepatic lipid accumulation and confers susceptibility to hepatic fibrosis and hepatocellular carcinoma. The aim of this study was to estimate the effect size of homozygosity for the PNPLA3 I148M variant (148M/M) on the fibrosis progression rate (FPR) and the interaction with age at infection in chronic hepatitis C (CHC).<h4>Methods</h4>FPR was estimated in a prospective cohort of 247 CHC patients without alcohol intake and diab ...[more]

PMID: 25171251

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Project description:The patatin-like phospholipase domain-containing protein 3 (PNPLA3) I148M variant predisposes to hepatic steatosis and progression to advanced liver injury with development of fibrosis, cirrhosis, and cancer. Hepatic stellate cells (HSCs) drive the wound healing response to chronic injury, and lack of liver X receptor (LXR) signaling exacerbates liver fibrogenesis by impairing HSC cholesterol homeostasis. However, the contribution of the I148M variant to this process is still unknown. We analyzed LXR expression and transcriptional activity in primary human HSCs and overexpressing LX-2 cells according to PNPLA3 genotype (wild type [WT] versus I148M). Here we demonstrate that LXR? protein increased whereas LXR target gene expression decreased during in vitro activation of primary human HSCs. Notably, LXR? levels and signaling were reduced in primary I148M HSCs compared to WT, as displayed by decreased expression of LXR target genes. Moreover, reduced expression of cholesterol efflux and enzymes generating oxysterols was associated with higher total and free cholesterol accumulation whereas endogenous cholesterol synthesis and uptake were diminished in I148M HSCs. Luciferase assays on LXR response element confirmed decreased LXR transcriptional activity in I148M HSCs; in contrast the synthetic LXR agonist T0901317 replenished LXR functionality, supported by adenosine triphosphate-binding cassette subfamily A member 1 (ABCA1) induction, and reduced collagen1?1 and chemokine (C-C motif) ligand 5 expression. Conversely, the peroxisome proliferator-activated receptor gamma (PPAR?) agonist rosiglitazone had only partial effects on the LXR target gene ABCA1, and neither diminished expression of proinflammatory cytokines nor increased de novo lipogenic genes in I148M HSCs. Conclusion: As a consequence of reduced PPAR? activity, HSCs carrying I148M PNPLA3 show impaired LXR signaling, leading to cholesterol accumulation. The use of a specific LXR agonist shows beneficial effects for diminishing sustained HSC activation and development of liver fibrogenesis.

Dataset Information

Interaction between PNPLA3 I148M variant and age at infection in determining fibrosis progression in chronic hepatitis C.

Background and aims

Methods

Results

Conclusions

Publications

Interaction between PNPLA3 I148M variant and age at infection in determining fibrosis progression in chronic hepatitis C.

Similar Datasets

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