NR1H4 rs35724 G>C variant modulates liver damage in nonalcoholic fatty liver disease

Grazia Pennisi, Rossella Zito, Stefania Grimaudo, Antonio Craxi, Salvatore Petta, Rosaria Maria Pipitone, Vito Di Marco, Mohammed Eslam, Guido Baselli, Miriam Longo, Stefano Romeo, Luca Valenti, Paola Dongiovanni, Anna Ludovica Fracanzani, Jussi Pihlajamäki, Daniele Prati, Hannele Yki-Järvinen, Jacob George

Risultato della ricerca: Articlepeer review

Abstract

Background and Aims: Farnesoid X receptor (FXR) plays a key role in bile acid and lipid homeostasis. Experimental evidence suggests that it can modulate liver damage related to nonalcoholic fatty liver disease (NAFLD). We examined the impact of the NR1H4 rs35724 G>C, encoding for FXR, on liver damage in a large cohort of patients at risk of steatohepatitis. Methods: We considered 2,660 consecutive individuals at risk of steatohepatitis with liver histology. The rs35724 G>C polymorphisms were genotyped by TaqMan assays. Gene expression was evaluated by RNASeq in a subset of patients (n = 124). Results: The NR1H4 rs35724 CC genotype, after adjusting for clinic-metabolic and genetic confounders and for enrolling centre, was protective against severity of steatosis (GG vs CC OR 0.77, 95% CI 0.62-0.95; P =.01), steatohepatitis (GG vs CC OR 0.62, 95% CI 0.47-0.83; P =.001) and severity of fibrosis (GG vs CC OR 0.83, 95% CI 0.67-0.98; P =.04). The C allele was associated with higher total circulating cholesterol (P =.01). Patients carrying the NR1H4 rs35724 C allele had significantly higher hepatic mRNA levels of FXR and were associated with higher hepatic FGFR4 and Cyp39A1 that are in turn involved in bile acid synthesis. Conclusions: Increased hepatic FXR expression due to the NR1H4 rs35724 C allele is linked to higher serum cholesterol but protects against steatosis, steatohepatitis and liver fibrosis. The translational relevance of these results for patient risk stratification and FXR-targeted therapy warrants further investigation.
Lingua originaleEnglish
pagine (da-a)1-8
Numero di pagine8
RivistaLiver International
Stato di pubblicazionePublished - 2021

All Science Journal Classification (ASJC) codes

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