Liepinsh 2024 Br J Pharmacol
| Liepinsh E, Zvejniece L, Clemensson L, Ozola M, Vavers E, Cirule H, Korzh S, Skuja S, Groma V, Briviba M, Grinberga S, Liu W, Olszewski P, Gentreau M, Fredriksson R, Dambrova M, SchiΓΆth HB (2024) Hydroxymethylglutaryl-CoA reductase activity is essential for mitochondrial Ξ²-oxidation of fatty acids to prevent lethal accumulation of long-chain acylcarnitines in the mouse liver. Br J Pharmacol [Epub ahead of print]. https://doi.org/10.1111/bph.16363 |
Liepinsh Edgars, Zvejniece Liga, Clemensson Laura, Ozola Melita, Vavers Edijs, Cirule Helena, Korzh Stanislava, Skuja Sandra, Groma Valerija, Briviba Monta, Grinberga Solveiga, Liu Wen, Olszewski Pawel, Gentreau Melissa, Fredriksson Robert, Dambrova Maija, Schioeth Helgi B (2024) Br J Pharmacol
Abstract: Statins are competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGCR), and exert adverse effects on mitochondrial function, although the mechanisms underlying these effects remain unclear. We used a tamoxifen-induced Hmgcr-knockout (KO) mouse model, a multi-omics approach and mitochondrial function assessments to investigate whether decreased HMGCR activity impacts key liver energy metabolism pathways.
We established a new mouse strain using the Cre/loxP system, which enabled whole-body deletion of Hmgcr expression. These mice were crossed with Rosa26Cre mice and treated with tamoxifen to delete Hmgcr in all cells. We performed transcriptomic and metabolomic analyses and thus evaluated time-dependent changes in metabolic functions to identify the pathways leading to cell death in Hmgcr-KO mice.
Lack of Hmgcr expression resulted in lethality, due to acute liver damage caused by rapid disruption of mitochondrial fatty acid Ξ²-oxidation and very high accumulation of long-chain (LC) acylcarnitines in both male and female mice. Gene expression and KO-related phenotype changes were not observed in other tissues. The progression to liver failure was driven by diminished peroxisome formation, which resulted in impaired mitochondrial and peroxisomal fatty acid metabolism, enhanced glucose utilization and whole-body hypoglycaemia.
Our findings suggest that HMGCR is crucial for maintaining energy metabolism balance, and its activity is necessary for functional mitochondrial Ξ²-oxidation. Moreover, statin-induced adverse reactions might be rescued by the prevention of LC acylcarnitine accumulation. β’ Keywords: HMGβCoA reductase, Rosa26Cre mice, Mitochondria, Statins, Tamoxifenβinduced knockout mouse model β’ Bioblast editor: Plangger M β’ O2k-Network Lab: LV Riga Liepins E
Labels: MiParea: Respiration, Genetic knockout;overexpression
Organism: Mouse
Tissue;cell: Liver
Preparation: Homogenate
Regulation: Inhibitor Coupling state: ET, LEAK, OXPHOS Pathway: F, N, S, NS, ROX HRR: Oxygraph-2k
2024-05
