Dietary Cholesterol Exacerbates Statin-Induced Hepatic Toxicity in Syrian Golden Hamsters and in Patients in an Observational Cohort Study.

PURPOSE: Statins are inhibitors of 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase, which is involved in cholesterol synthesis. The major side effects of statins include muscle- and liver-related toxicity. Muscle toxicity is highly associated with polymorphisms in cytochrome P450 proteins (CYPs), as predicted by pharmacogenomics. However, the mechanisms of hepatotoxicity are not well understood. Due to differences in cholesterol metabolism, statins are well tolerated in mice. In contrast, hamsters exhibit metabolic traits similar to humans and are suitable for studying the hepatotoxicity of statins. METHODS: We investigated the effect of rosuvastatin (RSV) on liver damage in wild-type (WT) hamsters fed a high-cholesterol diet (HCD) and LDLR knockout (LDLR-/-) hamsters that developed spontaneous hypercholesterolemia. Two cohorts of clinical subjects (clinical registry number: 2017001) taking atorvastatin (ATV) were recruited for direct (assessment of cholesterol intake individually, n = 44) and indirect (celebratory meals/holiday season, n = 1993) examination of dietary cholesterol intake and liver damage, as indicated by elevation of alanine aminotransferase (ALT). RESULTS: RSV at a dose of 10 mg/kg caused fatal liver damage only in HCD-fed WT hamsters, while LDLR-/- hamsters with the same cholesterol levels were resistant to this toxic effect. In the human studies, we observed that the incidence of hepatic toxicity in patients receiving long-term ATV treatment was higher in patients with greater dietary cholesterol intake and in patients who consumed more food during Chinese holidays. CONCLUSION: Our results propose, for the first time, that dietary cholesterol significantly contributes to statin-related hepatotoxicity, providing valuable insight into the clinical use of statins.

CRISPR/Cas9 based blockade of IL-10 signaling impairs lipid and tissue homeostasis to accelerate atherosclerosis.

Interleukin-10 (IL-10) is a widely recognized immunosuppressive factor. Although the concept that IL-10 executes an anti-inflammatory role is accepted, the relationship between IL-10 and atherosclerosis is still unclear, thus limiting the application of IL-10-based therapies for this disease. Emerging evidence suggests that IL-10 also plays a key role in energy metabolism and regulation of gut microbiota; however, whether IL-10 can affect atherosclerotic lesion development by integrating lipid and tissue homeostasis has not been investigated. In the present study, we developed a human-like hamster model deficient in IL-10 using CRISPR/Cas9 technology. Our results showed that loss of IL-10 changed the gut microbiota in hamsters on chow diet, leading to an increase in lipopolysaccharide (LPS) production and elevated concentration of LPS in plasma. These changes were associated with systemic inflammation, lipodystrophy, and dyslipidemia. Upon high cholesterol/high fat diet feeding, IL-10-deficient hamsters exhibited abnormal distribution of triglyceride and cholesterol in lipoprotein particles, impaired lipid transport in macrophages and aggravated atherosclerosis. These findings show that silencing IL-10 signaling in hamsters promotes atherosclerosis by affecting lipid and tissue homeostasis through a gut microbiota/adipose tissue/liver axis.

Tanshinone IIA alleviates hypoxia/reoxygenation induced cardiomyocyte injury via lncRNA AK003290/miR-124-5p signaling.

BACKGROUND: Acute myocardial infarction (AMI) is the leading cause of death globally and has thus placed a heavy burden on healthcare. Tanshinone IIA (TSA) is a major active compound, extracted from Salvia miltiorrhiza Bunge, that possesses various pharmacological activities. The aim of the present study was to investigate the role of TSA in AMI and its underlying mechanism of action. RESULTS: We have shown that TSA decreased the apoptosis rate, the amount of LDH, MDA as well as ROS of cardiomyocytes. Meantime, it elevated mitochondrial membrane potential (MMP) which was decreased by H/R treatment. It was also determined that miR-124-5p targets AK003290 directly. TSA up-regulated the expression of AK003290 and its function can be reversed by knock down of AK003290 as well as miR-124-5p overexpression. CONCLUSION: TSA exerts the protective role against H/R induced apoptosis, oxidative and MMP loss of cardiomyocytes via regulating AK003290 and miR-124-5p signaling.

An interspecies study of lipid profiles and atherosclerosis in familial hypercholesterolemia animal models with low-density lipoprotein receptor deficiency.

Small rodents, especially mice and rats, have been widely used in atherosclerosis studies even though humans exhibit completely different lipoprotein metabolism and atherosclerotic characteristics. Until recently, various rodent models of human familial hypercholesterolemia (FH) have been created, including mice, rats, and golden Syrian hamsters. Although hamsters reportedly possess metabolic features similar to humans, there is no systematic characterization of the properties of circulating lipids and atherosclerotic lesions in these rodent models. We used three FH animal species (mice, rats, and hamsters) with low-density lipoprotein receptor (Ldlr) deficiency to fully assess lipoprotein metabolism and atherosclerotic characteristics. Compared to chow diet-fed mice and rats, Ldlr knockout (KO) hamsters showed increased cholesterols in LDL fractions similar to human FH patients. Upon 12-week high-cholesterol/high-fat diet feeding, both heterozygous and homozygous Ldlr KO hamsters displayed hyperlipidemic phenotypes, whereas only homozygous Ldlr KO mice and rats showed only moderate increases in plasma lipid levels. Moreover, rats were resistant to diet-induced atherosclerosis compared to mice, and hamsters showed more atherosclerotic lesions in the aortas and coronary arteries. Further morphological study revealed that only hamsters developed atherosclerosis in the abdominal segments, which is highly similar to FH patients. This unique animal model will provide insight into the translational study of human atherosclerosis and could be useful for developing novel treatments for FH patients.

Patchouli alcohol protects against ischemia/reperfusion-induced brain injury via inhibiting neuroinflammation in normal and obese mice.

Almost all of the candidate drugs for ischemic stroke failed to be translated from bench to beside. One important reason is that animals used in experimental studies cannot mimic ischemic patients due to lack of comorbidities like hypertension, diabetes and obesity. Therefore, it is better to test candidate drugs not only in normal animals but also in animals with comorbidities. Patchouli alcohol (PA), a natural tricyclic sesquiterpene in the traditional Chinese herb Pogostemonisherba, is well recognized for its anti-inflammation function in various inflammatory diseases. And as inflammation plays a very important role in cerebral ischemia/reperfusion (I/R) injury process and determines the ultimate brain damage, we hypothesized that PA could protect against cerebral I/R injury through its anti-inflammation ability. In this study, the effects of PA on cerebral I/R injury were evaluated in normal mice and obese mice. In normal mice with cerebral I/R injury, PA treatment reduced the infarct volume and neurological deficits in a dose- and time-dependent manner. PA treatment alleviated BBB dysfunction, inhibited mRNA and protein levels of TNF-α and IL-1ß and modulated the activation of MAPKs signaling pathways. Moreover, PA also reduced infarct volume, alleviated the BBB dysfunction and inhibited inflammation in ob/ob mice with cerebral I/R injury. In conclusion, we demonstrated for the first time that PA could protect against cerebral I/R injury not only in normal mice but also in obese mice via inhibiting inflammation, suggesting that PA can be a potential drug for clinical treatment of ischemic stroke.