Population‐based meta‐analysis and gene‐set enrichment identifies FXR/RXR pathway as common to fatty liver disease and serum lipids

Abstract

Nonalcoholic fatty liver disease (NAFLD) is prevalent worldwide. NAFLD is associated with elevated serum triglycerides (TG), low‐density lipoprotein cholesterol (LDL), and reduced high‐density lipoprotein cholesterol (HDL). Both NAFLD and blood lipid levels are genetically influenced and may share a common genetic etiology. We used genome‐wide association studies (GWAS)–ranked genes and gene‐set enrichment analysis to identify pathways that affect serum lipids and NAFLD. We identified credible genes in these pathways and characterized missense variants in these for effects on serum traits. We used MAGENTA to identify 58 enriched pathways from publicly available TG, LDL, and HDL GWAS (n = 99,000). Three of these pathways were also enriched for associations with European‐ancestry NAFLD GWAS (n = 7176). One pathway, farnesoid X receptor (FXR)/retinoid X receptor (RXR) activation, was replicated for association in an African‐ancestry NAFLD GWAS (n = 3214) and plays a role in serum lipids and NAFLD. Credible genes (proteins) in FXR/RXR activation include those associated with cholesterol/bile/bilirubin transport/absorption (ABCC2 (MRP2) [ATP binding cassette subfamily C member (multidrug resistance‐associated protein 2)], ABCG5, ABCG8 [ATP‐binding cassette (ABC) transporters G5 and G8], APOB (APOB) [apolipoprotein B], FABP6 (ILBP) [fatty acid binding protein 6 (ileal lipid‐binding protein)], MTTP (MTP) [microsomal triglyceride transfer protein], SLC4A2 (AE2) [solute carrier family 4 member 2 (anion exchange protein 2)]), nuclear hormone–mediated control of metabolism (NR0B2 (SHP) [nuclear receptor subfamily 0 group B member 2 (small heterodimer partner)], NR1H4 (FXR) [nuclear receptor subfamily 1 group H member 4 (FXR)], PPARA (PPAR) [peroxisome proliferator activated receptor alpha], FOXO1 (FOXO1A) [forkhead box O1]), or other pathways (FETUB (FETUB) [fetuin B]). Missense variants in ABCC2 (MRP2), ABCG5 (ABCG5), ABCG8 (ABCG8), APOB (APOB), MTTP (MTP), NR0B2 (SHP), NR1H4 (FXR), and PPARA (PPAR) that associate with serum LDL levels also associate with serum liver function tests in UK Biobank. Conclusion: Genetic variants in NR1H4 (FXR) that protect against liver steatosis increase serum LDL cholesterol while variants in other members of the family have congruent effects on these traits. Human genetic pathway enrichment analysis can help guide therapeutic development by identifying effective targets for NAFLD/serum lipid manipulation while minimizing side effects. In addition, missense variants could be used in companion diagnostics to determine their influence on drug effectiveness.

Precision Medicine in Fatty Liver Disease/Non-Alcoholic Fatty Liver Disease

“…GAFLD is proposed to be characterized by the absence of primary dysmetabolic abnormalities and obesity and is thus considered to be driven mainly by genetic variants contributing to liver fat accumulation and damage [ 14 , 15 , 16 , 17 ]. A multitude of genes and genetic variants are being investigated for their impact on predisposition to NAFLD development, with prime examples described below [ 18 , 19 , 20 ].…”

“…In the microsomal TG transfer protein (MTTP), variants such as the rs2306986 (c.294G > C, p.E98D) and rs1800591 (−493G > T) can lead to increased hepatic TG content and impaired production/transportation of very low-density lipoprotein (VLDL), and thus a higher susceptibility to NAFLD [ 18 , 19 , 26 , 27 ]. Moreover, the rs641738 (C > T) variant of the membrane-bound O-acyltransferase domain-containing protein 7 (MBOAT7), which is highly expressed in liver and inflammatory cells, has also been associated with hepatic fat content, a higher risk of inflammation, more severe liver damage, increased risk of fibrosis, and HCC [ 20 ].…”

“…On the contrary, loss-of-function variants on the hydroxysteroid (17-beta) dehydrogenase-13 (HSD17B13) gene, such as the rs72613567, have been proposed to mitigate NAFLD’s progression to NASH, fibrosis, and hepatocellular carcinoma (HCC) by the loss of its enzymatic activity, which leads to increased retinol–binding protein (RBP4)–transthyretin (TTR) transport from hepatocytes [ 18 , 30 , 31 , 32 ]. Other variants associated with decreased lipid and transaminase levels include the A286V missense variant of the peroxisome proliferator-activated (PPAR) alpha receptor, which is highly expressed in the liver as part of the nuclear receptors’ superfamily and is a crucial regulator of lipid metabolism, beta-oxidation, and hepatic FA transport, as well as the G171A variant of the nuclear receptor subfamily 0 group B member 2 (SHP) [ 18 ]. All these variants need to be further studied to better determine their precise role in NAFLD pathophysiology in humans [ 33 ].…”

FXR agonists for MASH therapy: Lessons and perspectives from obeticholic acid

“…27 It also governs gluconeogenesis via phosphoenolpyruvate carboxykinase and glucose-6-phosphatase 13 as well as inhibits glycolysis via carbohydrate response element-binding protein 28 and glucagon-like peptide 1 (GLP-1). 29 Additionally, FXR activation promotes β-oxidation of fatty acids and regulate serum lipoprotein levels via peroxisome proliferator-activated receptor alpha, 30 sterol regulatory element-binding protein-1c, 31 apolipoprotein A-I, 32 apolipoprotein B, 33 and apolipoprotein C-II/III, 32 resulting in a reduction in hepatic fat content.…”