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Interaction between estrogen receptor-α and PNPLA3 p.I148M variant drives fatty liver disease susceptibility in women
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Interaction between estrogen receptor-α and PNPLA3 p.I148M variant drives fatty liver disease susceptibility in women
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Journal Article
Interaction between estrogen receptor-α and PNPLA3 p.I148M variant drives fatty liver disease susceptibility in women
2023
Overview
Fatty liver disease (FLD) caused by metabolic dysfunction is the leading cause of liver disease and the prevalence is rising, especially in women. Although during reproductive age women are protected against FLD, for still unknown and understudied reasons some develop rapidly progressive disease at the menopause. The patatin-like phospholipase domain-containing 3 (
PNPLA3
) p.I148M variant accounts for the largest fraction of inherited FLD variability. In the present study, we show that there is a specific multiplicative interaction between female sex and
PNPLA3
p.I148M in determining FLD in at-risk individuals (steatosis and fibrosis,
P
< 10
−10
; advanced fibrosis/hepatocellular carcinoma,
P
= 0.034) and in the general population (
P
< 10
−7
for alanine transaminase levels). In individuals with obesity, hepatic
PNPLA3
expression was higher in women than in men (
P
= 0.007) and in mice correlated with estrogen levels. In human hepatocytes and liver organoids,
PNPLA3
was induced by estrogen receptor-α (ER-α) agonists. By chromatin immunoprecipitation and luciferase assays, we identified and characterized an ER-α-binding site within a
PNPLA3
enhancer and demonstrated via CRISPR–Cas9 genome editing that this sequence drives
PNPLA3
p.I148M upregulation, leading to lipid droplet accumulation and fibrogenesis in three-dimensional multilineage spheroids with stellate cells. These data suggest that a functional interaction between ER-α and
PNPLA3
p.I148M variant contributes to FLD in women.
Analysis using a combination of molecular and genetic epidemiological approaches reveals an interaction between female sex and the genetic variant
PNPLA3
p.I148M that might explain why some women have increased susceptibility to fatty liver disease after onset of menopause.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ Acyltransferases - metabolism
/ Alanine
/ Animals
/ Biomedical and Life Sciences
/ Cardiology and Cardiovascular Disease
/ CRISPR
/ Female
/ Females
/ Fibrosis
/ Genetic Predisposition to Disease
/ Genomes
/ Humans
/ Kardiologi och kardiovaskulära sjukdomar
/ Lipids
/ Liver
/ Male
/ Mice
/ Non-alcoholic Fatty Liver Disease - genetics
/ Non-alcoholic Fatty Liver Disease - pathology
/ Phospholipases A2, Calcium-Independent - genetics
/ Phospholipases A2, Calcium-Independent - metabolism
/ Receptors, Estrogen - metabolism
/ Sex
/ Women
