Dataset Information

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.

SUBMITTER: Cherubini A

PROVIDER: S-EPMC10579099 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Cherubini Alessandro A Ostadreza Mahnoosh M Jamialahmadi Oveis O Pelusi Serena S Rrapaj Eniada E Casirati Elia E Passignani Giulia G Norouziesfahani Marjan M Sinopoli Elena E Baselli Guido G Meda Clara C Dongiovanni Paola P Dondossola Daniele D Youngson Neil N Tourna Aikaterini A Chokshi Shilpa S Bugianesi Elisabetta E Della Torre Sara S Prati Daniele D Romeo Stefano S Valenti Luca L

Nature medicine 20230925 10

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 ...[more]

PMID: 37749332

Similar Datasets

Project description:Background & aimsThe loss of ovarian functions defining menopause leads to profound metabolic changes and heightens the risk of developing metabolic dysfunction-associated steatotic liver disease (MASLD). Although estrogens primarily act on the female liver through estrogen receptor alpha (ERα), the specific contribution of impaired ERα signaling in triggering MASLD after menopause remains unclear.MethodsTo address this gap in knowledge, we compared the liver transcriptomes of sham-operated (SHAM) and ovariectomized (OVX) control and liver ERα knockout (LERKO) female mice by performing RNA-Seq analysis.ResultsOVX led to 1426 differentially expressed genes (DEGs) in the liver of control mice compared to 245 DEGs in LERKO mice. Gene ontology analysis revealed a distinct ovariectomy-induced modulation of the liver transcriptome in LERKO compared with controls, indicating that hepatic ERα is functional and necessary for the complete reprogramming of liver metabolism in response to estrogen depletion. Additionally, we observed an ovariectomy-dependent induction of male-biased genes, especially in the liver of control females, pointing to hepatic ERα involvement in the masculinization of the liver after estrogen loss. To investigate the translational relevance of such findings, we assessed liver samples from a cohort of 60 severely obese individuals (51 women; 9 men). Notably, a shift of the liver transcriptome toward a male-like profile was also observed only in obese women with MASLD (n = 43), especially in women ≥51 years old (15/15), suggesting that masculinization of the female liver contributes to MASLD development in obese women.ConclusionsThese results highlight the role of hepatic ERα in driving masculinization of the liver transcriptome following menopause, pointing to this receptor as a potential pharmacological target for preventing MASLD in post-menopausal women.Impact and implicationsDespite the increased risk of developing MASLD after menopause, the specific contribution of impaired hepatic estrogen signaling in driving MASLD in females has not been a major research focus, and, thus, has limited the development of tailored strategies that address the specific mechanisms underlying MASLD in post-menopausal women. This study reveals the functional role of hepatic ERα in mediating liver metabolic changes in response to estrogens loss, leading to a shift in the liver transcriptome towards a male-like profile. In women with obesity, this shift is associated with the development of MASLD. These findings underscore the potential of targeting hepatic ERα as a promising approach for developing effective, sex-specific treatments to preserve liver health and prevent or limit the development and progression of MASLD in post-menopausal women.

Project description:Background & aimsA number of genetic polymorphisms have been associated with susceptibility to or protection against non-alcoholic fatty liver disease (NAFLD), but the underlying mechanisms remain unknown. Here, we focused on the rs738409 C>G single nucleotide polymorphism (SNP), which produces the I148M variant of patatin-like phospholipase domain-containing protein 3 (PNPLA3) and is strongly associated with NAFLD.MethodsTo enable mechanistic dissection, we developed a human pluripotent stem cell (hPSC)-derived multicellular liver culture by incorporating hPSC-derived hepatocytes, hepatic stellate cells, and macrophages. We first applied this liver culture to model NAFLD by utilising a lipotoxic milieu reflecting the circulating levels of disease risk factors in affected individuals. We then created an isogenic pair of liver cultures differing only at rs738049 and compared NAFLD phenotype development.ResultsOur hPSC-derived liver culture recapitulated many key characteristics of NAFLD development and progression including lipid accumulation and oxidative stress, inflammatory response, and stellate cell activation. Under the lipotoxic conditions, the I148M variant caused the enhanced development of NAFLD phenotypes. These differences were associated with elevated IL-6/signal transducer and activator of transcription 3 (STAT3) activity in liver cultures, consistent with transcriptomic data of liver biopsies from individuals carrying the rs738409 SNP. Dampening IL-6/STAT3 activity alleviated the I148M-mediated susceptibility to NAFLD, whereas boosting it in wild-type liver cultures enhanced NAFLD development. Finally, we attributed this elevated IL-6/STAT3 activity in liver cultures carrying the rs738409 SNP to increased NF-κB activity.ConclusionsOur study thus reveals a potential causal link between elevated IL-6/STAT3 activity and 148M-mediated susceptibility to NAFLD.Impact and implicationsAn increasing number of genetic variants manifest in non-alcoholic fatty liver disease (NAFLD) development and progression; however, the underlying mechanisms remain elusive. To study these variants in human-relevant systems, we developed an induced pluripotent stem cell-derived multicellular liver culture and focused on a common genetic variant (i.e. rs738409 in PNPLA3). Our findings not only provide mechanistic insight, but also a potential therapeutic strategy for NAFLD driven by this genetic variant in PNPLA3. Our liver culture is therefore a useful platform for exploring genetic variants in NAFLD development.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets