Hydroxymethylglutaryl-CoA reductase activity is essential for mitochondrial β-oxidation of fatty acids to prevent lethal accumulation of long-chain acylcarnitines in the mouse liver.

Liepinsh, E ; Zvejniece, L ; et al.

In: British journal of pharmacology, 2024-04-19

academicJournal

Background and Purpose: 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.

Experimental Approach: We established a new mouse strain using the Cre/loxP system, which enabled whole-body deletion of Hmgcr expression. These mice were crossed with Rosa26 Cre 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.

Key Results: Lack of Hmgcr expression resulted in lethality, due to acute liver damage caused by rapid disruption of mitochondrial fatty acid β-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.

Conclusion and Implications: Our findings suggest that HMGCR is crucial for maintaining energy metabolism balance, and its activity is necessary for functional mitochondrial β-oxidation. Moreover, statin-induced adverse reactions might be rescued by the prevention of LC acylcarnitine accumulation.

Titel:	Hydroxymethylglutaryl-CoA reductase activity is essential for mitochondrial β-oxidation of fatty acids to prevent lethal accumulation of long-chain acylcarnitines in the mouse liver.
Autor/in / Beteiligte Person:	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 ; Schiöth, HB
Zeitschrift:	British journal of pharmacology, 2024-04-19
Veröffentlichung:	Ahead of Print, 2024
Medientyp:	academicJournal
ISSN:	1476-5381 (electronic)
DOI:	10.1111/bph.16363
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article Language: English [Br J Pharmacol] 2024 Apr 19. <i>Date of Electronic Publication: </i>2024 Apr 19. References: Ahmad, T., Kelly, J. P., McGarrah, R. W., Hellkamp, A. S., Fiuzat, M., Testani, J. M., Wang, T. S., Verma, A., Samsky, M. D., Donahue, M. P., Ilkayeva, O. R., Bowles, D. E., Patel, C. B., Milano, C. A., Rogers, J. G., Felker, G. M., O'Connor, C. M., Shah, S. H., & Kraus, W. E. (2016). Prognostic implications of long‐chain acylcarnitines in heart failure and reversibility with mechanical circulatory support. Journal of the American College of Cardiology, 67(3), 291–299. https://doi.org/10.1016/j.jacc.2015.10.079. ; Alexander, S. P., Fabbro, D., Kelly, E., Mathie, A., Peters, J. A., Veale, E. L., Armstrong, J. F., Faccenda, E., Harding, S. D., Pawson, A. J., Southan, C., Davies, J. A., Annett, S., Boison, D., Burns, K. E., Dessauer, C., Gertsch, J., Helsby, N. A., Izzo, A. A., … Wong, S. S. 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