Mevalonolactone is an intermediate metabolite in the eukaryotic mevalonate pathway, serving as the stable δ-lactone form of mevalonate with oral activity. Mevalonolactone exhibits binding affinity for ZNF384 ( K a = 12.6 μM) and inhibitory activity against aconitase ( aconitase ). Mevalonolactone promotes the nuclear localization of ZNF384 and enhances its binding to the GGPPS promoter. Mevalonolactone induces insulin resistance, disrupts glucose and lipid metabolism, enhances the isoprenylation of K-Ras, and inhibits the activation of the insulin signaling pathway. Mevalonolactone inhibits polypeptide synthesis of HMG-CoA reductase in isolated rat hepatocytes, promotes its degradation, and reduces its enzymatic activity. Mevalonolactone impairs mitochondrial function in rat brains. Mevalonolactone promotes the development of metabolically unhealthy obesity. Mevalonolactone can be used in research related to metabolically abnormal obesity, mevalonic aciduria, HMGCR -related limb-girdle myopathy, and statin-induced myopathy [1] [2] [3] [4].
In Vivo, Mevalonolactone (10 mM; i.p.; once every 2 days; for 6 consecutive weeks) induces metabolically abnormal obesity in male C57BL/6J mice fed a normal diet. Through upregulating GGPPS, enhancing K-Ras isoprenylation, and ZNF384-mediated transcriptional activation of *Ggpps*, it triggers insulin resistance, impaired glucose homeostasis, increased body and tissue weights, elevated triglyceride levels, as well as altered gene expression in the liver and adipose tissue[1]. Mevalonolactone (10 mM; i.p.; once every 2 days; for 6 consecutive weeks) exacerbates insulin resistance and glucose-lipid metabolic disorders in male C57BL/6J mice fed a high-fat diet, and promotes metabolically unhealthy obesity[1]. Mevalonolactone (200 mg/kg; p.o.; daily administration; for 14 consecutive days) significantly alleviates statin-induced myopathy symptoms in C57BL/6 mice, restoring their muscle strength, endurance and spontaneous activity to levels close to those of the control group[3].
In Vitro, Mevalonolactone directly binds to recombinant ZNF384 protein with a Kd value of 12.6 μM[1]. Mevalonolactone (1 μM; 24 h) enhances isoprenylation and membrane localization of K-Ras in AML12 cells, upregulates the protein level of GGPPS in cells, and inhibits insulin-stimulated AKT phosphorylation[1]. Mevalonolactone treatment promotes the nuclear localization of ZNF384 in cultured cells and enhances the binding of ZNF384 to the Ggpps promoter in cells[1]. Mevalonolactone (1 mM; added 50 seconds pre-Ca2+, measurements taken 100 seconds post-Ca2+) reduces the mitochondrial membrane potential of Ca2+-loaded rat brain mitochondria[2]. Mevalonolactone (1 mM; added 50 seconds pre-Ca2+, measurements 100 seconds post-Ca2+) reduces the mitochondrial matrix NAD (P) H content in Ca2+-loaded rat brain mitochondria, induces swelling in Ca2+-loaded rat brain mitochondria, and decreases the Ca2+ retention capacity of rat brain mitochondria[2]. Mevalonolactone (1-2 mM; 30-minute incubation at 37°C) induces lipid peroxidation in rat brain mitochondria, significantly increases MDA levels, and inhibits aconitase activity in rat brain mitochondria[2]. Mevalonolactone (1 μM-10 mM; 5 min-3 h) specifically reduces the activity of HMG-CoA reductase in rat hepatocytes[4].
References:
[1]. Nie HY, et al. Elevated mevalonolactone from Ruminococcus torques contributes to metabolically unhealthy obesity development. J Biol Chem. 2025;301(6):110281.
[2]. Cecatto C, et al. Mevalonolactone disrupts mitochondrial functions and induces permeability transition pore opening in rat brain mitochondria: Implications for the pathogenesis of mevalonic aciduria. Neurochem Int. 2017;108:133-145.
[3]. Yogev Y, et al. Limb girdle muscular disease caused by HMGCR mutation and statin myopathy treatable with mevalonolactone. Proc Natl Acad Sci U S A. 2023;120(7):e2217831120.
[4]. Edwards PA, et al. Mevalonolactone inhibits the rate of synthesis and enhances the rate of degradation of 3-hydroxy-3-methylglutaryl coenzyme A reductase in rat hepatocytes. J Biol Chem. 1983;258(12):7272-7275.
In Vivo, Mevalonolactone (10 mM; i.p.; once every 2 days; for 6 consecutive weeks) induces metabolically abnormal obesity in male C57BL/6J mice fed a normal diet. Through upregulating GGPPS, enhancing K-Ras isoprenylation, and ZNF384-mediated transcriptional activation of *Ggpps*, it triggers insulin resistance, impaired glucose homeostasis, increased body and tissue weights, elevated triglyceride levels, as well as altered gene expression in the liver and adipose tissue[1]. Mevalonolactone (10 mM; i.p.; once every 2 days; for 6 consecutive weeks) exacerbates insulin resistance and glucose-lipid metabolic disorders in male C57BL/6J mice fed a high-fat diet, and promotes metabolically unhealthy obesity[1]. Mevalonolactone (200 mg/kg; p.o.; daily administration; for 14 consecutive days) significantly alleviates statin-induced myopathy symptoms in C57BL/6 mice, restoring their muscle strength, endurance and spontaneous activity to levels close to those of the control group[3].
In Vitro, Mevalonolactone directly binds to recombinant ZNF384 protein with a Kd value of 12.6 μM[1]. Mevalonolactone (1 μM; 24 h) enhances isoprenylation and membrane localization of K-Ras in AML12 cells, upregulates the protein level of GGPPS in cells, and inhibits insulin-stimulated AKT phosphorylation[1]. Mevalonolactone treatment promotes the nuclear localization of ZNF384 in cultured cells and enhances the binding of ZNF384 to the Ggpps promoter in cells[1]. Mevalonolactone (1 mM; added 50 seconds pre-Ca2+, measurements taken 100 seconds post-Ca2+) reduces the mitochondrial membrane potential of Ca2+-loaded rat brain mitochondria[2]. Mevalonolactone (1 mM; added 50 seconds pre-Ca2+, measurements 100 seconds post-Ca2+) reduces the mitochondrial matrix NAD (P) H content in Ca2+-loaded rat brain mitochondria, induces swelling in Ca2+-loaded rat brain mitochondria, and decreases the Ca2+ retention capacity of rat brain mitochondria[2]. Mevalonolactone (1-2 mM; 30-minute incubation at 37°C) induces lipid peroxidation in rat brain mitochondria, significantly increases MDA levels, and inhibits aconitase activity in rat brain mitochondria[2]. Mevalonolactone (1 μM-10 mM; 5 min-3 h) specifically reduces the activity of HMG-CoA reductase in rat hepatocytes[4].
References:
[1]. Nie HY, et al. Elevated mevalonolactone from Ruminococcus torques contributes to metabolically unhealthy obesity development. J Biol Chem. 2025;301(6):110281.
[2]. Cecatto C, et al. Mevalonolactone disrupts mitochondrial functions and induces permeability transition pore opening in rat brain mitochondria: Implications for the pathogenesis of mevalonic aciduria. Neurochem Int. 2017;108:133-145.
[3]. Yogev Y, et al. Limb girdle muscular disease caused by HMGCR mutation and statin myopathy treatable with mevalonolactone. Proc Natl Acad Sci U S A. 2023;120(7):e2217831120.
[4]. Edwards PA, et al. Mevalonolactone inhibits the rate of synthesis and enhances the rate of degradation of 3-hydroxy-3-methylglutaryl coenzyme A reductase in rat hepatocytes. J Biol Chem. 1983;258(12):7272-7275.