<i>NR1H4</i> rs35724 G>C Variant Modulates Liver Damage in Nonalcoholic Fatty Liver Disease

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 variant, 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 was genotyped by TaqMan assays. Gene expression was evaluated by RNASeq in a subset of patients (n=124). Results: The NR1H4 rs35724 variant was protective against severity of steatosis (OR 0.89, 95% C.I. 0.80-0.98; p=0.02), steatohepatitis (OR 0.83, 95% C.I. 0.73-0.94; p=0.004) and severity of fibrosis (OR 0.89, 95% C.I. 0.80-0.99; p=0.03), these results were confirmed after adjusting for clinico-metabolic and genetic confounders. The variant was associated with higher total circulating cholesterol (p=0.01). Patients carrying the NR1H4 rs35724 variant had significantly higher hepatic mRNA levels of FXR and associated with higher hepatic FGFR4 and Cyp39A1 that are in turn involved in bile acid synthesis. Conclusions: Increased hepatic FXR expression due to rs35724 variant 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. Funding Statement: None. Declaration of Interests: None to declare. Ethics Approval Statement: Approval was obtained from the Internal Review Boards and their Ethics Committees, and written informed consent for the study was obtained from all controls and patients.