Statin-Induced Liver Injury Involves Cross-Talk between Cholesterol and Selenoprotein Biosynthetic Pathways

Abstract

Statins have become the mainstay of hypercholesterolemia treatment. Despite a seemingly clear rationale behind their use, the inhibition of HMG-CoA reductase, these compounds have been shown to elicit a variety of unanticipated and elusive effects and side effects in vivo. Among the most frequently noted side effects of statin treatment are elevations in liver enzymes. Here, we report our finding that atorvastatin, cerivastatin, and lovastatin at clinically common concentrations induce a selective, differential loss of selenoprotein expression in cultured human HepG2 hepatocytes. The primarily affected selenoprotein was glutathione peroxidase (GPx), whose biosynthesis, steady-state expression level, and catalytic activity were significantly reduced with 10 to 100 nM concentrations of the different compounds. Messenger RNA levels of GPx1 and GPx4 were unaffected by statin treatment, pointing at a posttranscriptional mechanism of selenoprotein suppression. Although statins at selenoprotein-modulatory doses were not cytotoxic by themselves, they induced a significantly increased sensitivity of the cells to peroxides, an effect that was largely reversible by supraphysiological concentrations of selenite. We conclude that statins inhibit the expression of inducible selenoproteins by preventing the mevalonate-dependent maturation of the single human selenocysteine-tRNA and may thereby evoke an increased vulnerability of the liver to secondary toxins. Selenoprotein modulation might constitute an important mechanism of statins to bring forth their clinical effects.

Nutritional Status Affects Fluvastatin-Induced Hepatotoxicity and Myopathy in Rats

“…We previously showed that feeding rats the HF diet for 8 weeks produced severe hepatic steatosis that was associated with hepatic injury caused by xenobiotics such as phenobarbital and dexamethasone via induction of CYP2B and CYP3A (Sugatani et al, 2006). Although the exact mechanism responsible for the liver injury in HF diet-fed rats is unclear, Kromer and Moosmann (2009) have reported that statins inhibit the expression of inducible selenoproteins by preventing the mevalonate-dependent maturation of human selenocysteine-tRNA and may thereby increase the vulnerability of the liver to secondary toxins such as peroxides. However, it remains to be elucidated whether fluvastatin-induced liver injury in HF diet-fed rats results from increased production of peroxides and/or increased sensitivity to peroxides due to cross-talk between the pathways of cholesterol and selenoprotein biosynthesis.…”

Statin or fibrate chronic treatment modifies the proteomic profile of rat skeletal muscle

“…Statin by inhibiting cholesterol biosynthesis may also affect glutathione peroxidase liver production, whose expression level and catalytic activity were reduced. The consequence of this loss may be an increased sensitivity of the cells to peroxide [33].…”

Metabolic networks in ferroptosis (Review)

“…Furthermore, human prostate cancer PC3 cells treated with atorvastatin undergo autophagy, whereas simvastatin leads to the induction of apoptosis in HCT116 colorectal cancer cells and renal cell carcinoma cells (41). Statins also downregulate the mevalonate pathway and block the biosynthesis of cellular isoprenoids, including IPP, which are responsible for the post-translational modification of Sec-tRNA [Ser]Sec and the synthesis of GPX4 (6,35,42). Although there is no experimental evidence demonstrating the link between statins and ferroptosis, statins downregulate the mevalonate pathway, which is a crucial signaling event for GPX4 maturation.…”