Atorvastatin Induces Hepatotoxicity in Diabetic Rats via Oxidative Stress, Inflammation, and Anti-Apoptotic Pathway

Abstract

BackgroundPatients with diabetes mellitus (DM) commonly receive statins to suppress vulnerability to adverse cardiovascular events. It has been clinically proven that hepatotoxicity is one of the most severe adverse effects of statins.Material/MethodsWe constructed diabetic rat models by feeding rats with high-fat food and by injection of low-dose STZ. Rats were randomized into 2 groups: a DM group (n=10) and a control (CON) group (n=5). CON rats received a normal diet, whereas DM rats ate high-fat food. Rats in the DM group underwent intraperitoneal STZ (35 mg/kg) injection following 6-week diet restriction. On the seventh day following STZ or blank injection, rats with FBG concentration over 11.1 mM were regarded as successfully established models and were used for further research.ResultsWe showed that severe liver injury occurred in diabetic rats treated with 20 mg/kg atorvastatin, as evidenced by attenuation of liver enzyme activities, elevation of bilirubin levels, and alterations in the hepatic architecture, including hepatocyte death by necrosis, lymphocyte infiltration, and fibrosis. We also found that atorvastatin increased the secretion of pro-inflammatory factors such as L-1, TNF, IL-6, and IL-18 by enhancing activation of the NF-B signal pathway in the livers of diabetic rats. Atorvastatin elevated the levels of ROS and reduced the antioxidant enzyme (SOD and CAT) activities. Atorvastatin also increased the expression of anti-apoptotic protein BCL2 and decreased the expression of pro-apoptotic protein BAX in the livers of diabetic rats.ConclusionAtorvastatin exerts potentially hepatotoxic effects on diabetic rats by modulating oxidative/antioxidative status, pro-inflammatory cytokine production, and apoptosis inhibition.

The Intestinal Effect of Atorvastatin: Akkermansia muciniphila and Barrier Function

“…The transcriptome of pancreatic islets from mice with similar Ator treatment has also shown activated NF-κB signaling and enhanced metabolic inflammation (Shen et al, 2020). Though the anti-inflammatory effects of statins have been reported in traumatic brain injury, HFD-induced renal injury, endothelial dysfunction, and cardiac and adipose tissue (Golia et al, 2014;Xu et al, 2017;Yamada et al, 2017;da Silva et al, 2018;Pengrattanachot et al, 2020), it has been reported that statins can induce insulin resistance via activation of caspase-1/IL-1β inflammasomes in adipose tissue (Henriksbo et al, 2019) and Ator could trigger liver toxicity in diabetic rats by promoting the generation of inflammation (Zeng and Liu, 2019). Moreover, we did not find that Ator could directly alter the NF-κB signaling pathway in Caco 2 cells.…”

Effect of prenatal exposure to Benzo[a]pyrene on ovarian toxicity and reproductive dysfunction: Protective effect of atorvastatin in the embryonic period

“…Therapeutic and biological properties of ATV at low doses are anti-inflammatory (10 mg/kg for 10 days), 9 antioxidant (0.1 and 1 mg/kg for 6 weeks), 10 and anti-apoptotic 9 properties. Complications of high doses of atorvastatin have been reported in some organs, such as, the liver (20 mg/kg for 10 days), 11 kidney (150 mg/ kg/day for 7 days), 12 and testis. 13 But, Lori et al stated atorvastatin at low doses have no side effects on fertility and reproduction in male and female rats.…”

Protective Role of Loranthus regularis against Liver Dysfunction, Inflammation, and Oxidative Stress in Streptozotocin Diabetic Rat Model

“…Moreover, the hepatocyte injury results in complex biological events that include neutrophil infiltration and activation of Kupffer cells. Such response stimulates apoptotic pathways and the release of inflammatory cytokines [ 8 ].…”