SFEIES24 Plenary Orals Plenary Orals (2 abstracts)
Damaging mutations in LXRα uncouple lipogenesis from hepatotoxicity and implicate hepatic cholesterol sensing in human liver health
Sam Lockhart 1 , Milan Muso 1 , Ilona Zvetkova 1 , Brian Lam 1 , Allessandra Ferrari 2 , Erik Schoenmakkers 1 , Katie Duckett 1 , Jack Leslie 3 , Beatriz Romartínez-Alonso 4 , John Tadross 1 , Raina Jia 1 , Eugene Gardner 1 , Katherine Kentistou 1 , Yajie Zhao 1 , Felix Day 1 , Alexander Mörseburg 1 , Kara Rainbow 1 , Deb Rimmington 1 , Matteo Mastantuoni 1 , James Harrison 1 , Meritxell Nus 1 , Khalid Guma’a 1 , Sam Sherratt-Mayhew 1 , Xiao Jiang 5 , Katherine Smith 5 , Dirk Paul 5 , Ben Jenkins 1 , Albert Koulman 1 , Maik Pietzner 1 , Claudia Langenberg 1 , Nick Wareham 1 , John Schwabbe 4 , Krish Chatterjee 1 , Fiona Oakley 3 , Derek Mann 3 , Peter Tontonoz 2 , Anthony Coll 1 , Ken Ong 1 , John Perry 1 & Stephen O’Rahilly 1
1University of Cambridge, Cambridge, United Kingdom; 2UCLA, LA, USA; 3University of Newcastle, Newcastle, United Kingdom; 4University of Leicester, Leicester, United Kingdom; 5Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom
The nuclear receptor LXRa activates lipogenic gene expression in hepatocytes. Its inhibition has been proposed as a strategy to treat MASLD. To understand the impact of reducing LXRa activity on human health we examined the association between the carriage of rare loss of function mutations in NR1H3 (encoding LXRa) and metabolic and hepatic phenotypes. We identified 63 rare predicted damaging variants in the ligand binding domain of LXRa in 454,787 participants in UK Biobank. On functional characterisation, 42 of these were found to be severely impaired. Consistent with loss of the lipogenic actions of LXRa, carriers of damaging mutations in LXRa had reduced serum triglycerides (ß=-0.13 s.d. ±0.03, P = 2.7x10-5, N(carriers)=971). Surprisingly, these carriers also had elevated serum liver enzymes (e.g. ALT: ß=0.17s.d. ±0.03, P = 1.1x10-8, N(carriers)=972) with a 35% increased risk of clinically significant elevations in ALT (OR=1.32, 95%CI:1.15-1.53, P = 1.2x10-4, N(carriers)=972), suggestive of hepatotoxicity. We generated a knock-in mouse carrying one of the most severely damaging mutations (Nr1h3 p.W441R) which we demonstrated to have dominant negative properties. Thse mice developed severe hepatitis and fibrotic liver injury when fed a western diet, despite markedly reduced steatosis, liver triglycerides and lipogenic gene expression. This phenotype was rescued by viral over-expression of wildtype LXRa specifically in hepatocytes, indicating a cell-autonomous effect of the mutant on hepatocyte health. While homozygous LXRa-KO mice showed some evidence of hepatocyte injury, the phenotype of the LXRaW441R/W441R mouse was much more severe, suggesting mutations that co-repress target genes can result in pathological impacts more severe than those seen with simple absence of the receptor. Taken together, our findings implicate LXRa in the maintenance of human liver health, identify a new murine model of rapidly progressive fibrotic liver disease and caution against LXR antagonism as a therapeutic strategy for MASLD.
Volume 104
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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