Interaction between estrogen receptor-α and PNPLA3 p.I148M variant drives fatty liver disease susceptibility in women

Abstract

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.

Time variation of high-risk groups for liver function deteriorations within fluctuating long-term liver function after hepatic radiotherapy in patients with hepatocellular carcinoma

“…Previous studies have indicated that sex hormones and sex hormone-binding globulin are associated with LF, liver fat, and liver disease [ 32 , 33 ]. Estrogen and estrogen receptor alpha may contribute to fatty liver and chronic liver diseases in women [ 34 – 36 ]. Furthermore, sex-dependent differences in cholestasis have also been reported [ 37 ].…”

Endogenous sex hormones and nonalcoholic fatty liver disease in US adults

“…31 Carriers of the p.I148M variant who persist in relatively high estradiol resulting from oestrone conversion in hepatocytes can synergize with insulin resistance and inflammation-mediated mechanisms, which result in hepatic fat accumulation. 31 We also assumed that oestrogen deficiency alone may be insufficient to cause NAFLD among postmenopausal women but that effects from other factors, metabolic risk factors, genetic predisposition, dietary factors, etc., may be amplified within the context of oestrogen deficiency. 32 A significant inverse association between total testosterone and NAFLD in men may be partly explained by hyperinsulinemia, 33,34 diabetes, 27,28 increased inflammatory cytokines, 35,36 and increased intestinal permeability due to sex hormone deficiency.…”

Association of metabolic-dysfunction associated steatotic liver disease with polycystic ovary syndrome

“… 51 The effect of the PNPLA3 I148M variant is larger in women than in men. 52 Given that PNPLA3 I148M is the most robust genetic variant associated with MAFLD, and there is strong association between this mutation and metabolism, it suggests a potential connection with metabolic symptoms in patients with PCOS. However, due to the lack of related research, more studies are needed to identify the underlying links.…”