HMG-CoA reductase deficiency results in disturbed fatty acid β-oxidation and accumulation of long-chain acylcarnitines in the mouse liver

HMG-CoA reductase (HMGCR) is a pivotal enzyme in the cholesterol and isoprenoid biosynthesis pathway and is the target of statin drugs widely used for cholesterol-lowering therapy, especially among the elderly in Western countries. Despite statin efficacy, 5-30% of patients experience side effects, leading to reduced adherence. The mechanisms behind these adverse reactions, particularly in the liver and muscles, remain elusive. To address this, we employed the Cre/loxP system to create a tamoxifen-inducible Hmgcr-knockout mouse model, allowing us to explore the impact of reduced HMGCR activity on liver mitochondrial and peroxisomal energy metabolism. Transcriptomic and metabolomic analyses, along with mitochondrial function assessment, unveiled time-dependent changes in metabolic functions. The Hmgcr-KO mice exhibited early-onset lethal liver failure, characterized by significantly elevated ALAT concentrations (600 U/L). High-resolution respirometry measurements revealed a marked decrease in mitochondrial respiration rates in liver tissues. The further progression of liver failure stemmed from peroxisome dysfunction, followed by impaired mitochondrial and peroxisomal fatty acid metabolism, resulting in heightened glucose utilization in the liver and subsequent whole-body hypoglycemia. At the study endpoint, the mitochondrial fatty acid oxidation rate decreased significantly by 2- to 3-fold. Dysfunctional mitochondrial and peroxisomal β-oxidation of long-chain fatty acids led to a remarkable up to 8-fold accumulation of long-chain acylcarnitines. Our findings underscore the crucial role of HMGCR in maintaining effective mitochondrial and peroxisomal β-oxidation in the liver, impacting whole-body energy homeostasis. Addressing the prevention of long-chain acylcarnitine accumulation emerges as a potential novel therapeutic strategy for metabolic liver diseases and statin intolerance.