Atorvastatin regulates hepatic transcriptome PXR dependently but distinct from pregnenolone 16α-carbonitrile and does not induce PXR-mediated liver steatosis

ABSTRACT: Several drugs induce liver steatosis through pregnane X receptor (PXR)-mediated mechanism. Atorvastatin is a PXR ligand but is still safe even in patients with metabolic dysfunction-associated steatotic liver disease. To reveal differences between atorvastatin and other PXR ligands, we characterized the effect of atorvastatin on PXR-mediated gene regulation and liver steatosis in mice. Mice were treated orally with atorvastatin, a classical PXR ligand pregnenolone 16α-carbonitrile (PCN), or pravastatin, a statin not activating PXR. Atorvastatin treatment was also performed in PXR knockout mice. Analysis of liver transcriptomics after four-day treatment indicated that atorvastatin regulates genes almost exclusively through PXR. Atorvastatin and PCN regulated partially overlapping, but distinct set of genes and Cyp3a11 was not induced by atorvastatin. Pathway analysis indicated that the atorvastatin treatment predominantly induced genes involved in cholesterol synthesis, while PCN affected pathways involved in growth, proliferation, and steatosis. PCN increased nuclear SREBP1 protein level while atorvastatin increased both SREBP1 and SREBP2. In high-fat diet (HFD)-fed mice, 28-day oral treatment with PCN aggravated diet-induced liver steatosis while atorvastatin had no effect. 28-day atorvastatin treatment reduced the hepatic expression of PXR, and its effect on cholesterol synthesis genes disappeared. PCN did not influence PXR expression, and the Cyp3a11 expression remained induced still after 28 days. Among the lipogenic genes studied, Scd1 was the only one significantly induced by PCN after 28-day treatment in the HFD-fed mice. In summary, atorvastatin regulates mouse liver transcriptomics PXR dependently but differently from PCN and represses PXR in long-term treatment in the HFD-fed mice. Unlike PCN, atorvastatin does not promote liver steatosis.

ORGANISM(S): Mus musculus

PROVIDER: GSE297644 | GEO | 2026/05/19

REPOSITORIES: GEO