Ochratoxin A Induces Steatosis via PPARγ-CD36 Axis.
Ontology highlight
ABSTRACT:
SUBMITTER: Zheng QW
PROVIDER: S-EPMC8620754 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Background and Aims. Angiotensin converting enzyme 2 (ACE2) is an important component of the renin-angiotensin system. Since angiotensin peptides have been shown to be involved in hepatic steatosis, we aimed to evaluate the hepatic lipid profile in ACE2-deficient (ACE2-/y) mice. Methods. Male C57BL/6 and ACE2-/y mice were analyzed at the age of 3 and 6 months for alterations in the lipid profiles of plasma, faeces, and liver and for hepatic steatosis. Results. ACE2-/y mice showed lower body weight and white adipose tissue at all ages investigated. Moreover, these mice had lower levels of cholesterol, triglycerides, and nonesterified fatty acids in plasma. Strikingly, ACE2-/y mice showed high deposition of lipids in the liver. Expression of CD36, a protein involved in the uptake of triglycerides in liver, was increased in ACE2-/y mice. Concurrently, these mice exhibited an increase in hepatic oxidative stress, evidenced by increased lipid peroxidation and expression of uncoupling protein 2, and downregulation of sirtuin 1. ACE2-/y mice also showed impairments in glucose metabolism and insulin signaling in the liver. Conclusions. Deletion of ACE2 causes CD36/sirtuin 1 axis impairment and thereby interferes with lipid homeostasis, leading to lipodystrophy and steatosis.
| S-EPMC5215286 | biostudies-literature
Project description:Curcumin has the potential to cure dyslipidemia and nonalcoholic fatty liver disease (NAFLD). However, its therapeutic effects are curbed by poor bioavailability. Our previous work has shown that modification of curcumin with polyethylene glycol (PEG) improves blood concentration and tissue distribution. This study sought to investigate the role of a novel PEGylated curcumin derivative (Curc-mPEG454) in regulating hepatic lipid metabolism and to elucidate the underlying molecular mechanism in a high-fat-diet- (HFD-) fed C57BL/6J mouse model. Mice were fed either a control chow diet (D12450B), an HFD (D12492) as the NAFLD model, or an HFD with Curc-mPEG454 administered by intraperitoneal injection at 50?mg/kg or 100?mg/kg for 16 weeks. We found that Curc-mPEG454 significantly lowered the body weight and serum triglyceride (TG) levels and reduced liver lipid accumulation in HFD-induced NAFLD mice. It was also shown that Curc-mPEG454 suppressed the HFD-induced upregulated expression of CD36 and hepatic peroxisome proliferator activated receptor-? (PPAR-?), a positive regulator of CD36. Moreover, Curc-mPEG454 dramatically activated cAMP response element-binding (CREB) protein, which negatively controls hepatic PPAR-? expression. These findings suggest that Curc-mPEG454 reverses HFD-induced hepatic steatosis via the activation of CREB inhibition of the hepatic PPAR-?/CD36 pathway, which may be an effective therapeutic for high-fat-diet-induced NAFLD.
| S-EPMC5523402 | biostudies-literature
Project description:Periodontal diseases have been reported to have a multidirectional association with metabolic disorders. We sought to investigate the correlation between periodontitis and diabetes or fatty liver disease using HFD-fed obese mice inoculated with P. gingivalis. Body weight, alveolar bone loss, serological biochemistry, and glucose level were determined to evaluate the pathophysiology of periodontitis and diabetes. For the evaluation of fatty liver disease, hepatic nonalcoholic steatohepatitis (NASH) was assessed by scoring steatosis, inflammation, hepatocyte ballooning and the crucial signaling pathways involved in liver metabolism were analyzed. The C-reactive protein (CRP) level and NASH score in P. gingivalis-infected obese mice were significantly elevated. Particularly, the extensive lobular inflammation was observed in the liver of obese mice infected with P. gingivalis. Moreover, the expression of metabolic regulatory factors, including peroxisome proliferator-activated receptor γ (Pparγ) and the fatty acid transporter Cd36, was up-regulated in the liver of P. gingivalis-infected obese mice. However, inoculation of P. gingivalis had no significant influence on glucose homeostasis, insulin resistance, and hepatic mTOR/AMPK signaling. In conclusion, our results indicate that P. gingivalis can induce the progression of fatty liver disease in HFD-fed mice through the upregulation of CD36-PPARγ axis. [BMB Reports 2021; 54(6): 323-328].
| S-EPMC8249874 | biostudies-literature
Project description:Circadian rhythm is involved in the development and diseases of many tissues. However, as an essential environmental regulating factor, its effect on amelogenesis has not been fully elucidated. The present study aims to investigate the correlation between circadian rhythm and ameloblast differentiation and to explore the mechanism by which circadian genes regulate ameloblast differentiation. Circadian disruption models were constructed in mice for in vivo experiments. An ameloblast-lineage cell (ALC) line was used for in vitro studies. As essential molecules of the circadian system, Bmal1 and Per2 exhibited circadian expression in ALCs. Circadian disruption mice showed reduced amelogenin (AMELX) expression and enamel matrix secretion and downregulated expression of BMAL1, PER2, PPARγ, phosphorylated AKT1 and β-catenin, cytokeratin-14 and F-actin in ameloblasts. According to previous findings and our study, BMAL1 positively regulated PER2. Therefore, the present study focused on PER2-mediated ameloblast differentiation and enamel formation. Per2 knockdown decreased the expression of AMELX, PPARγ, phosphorylated AKT1 and β-catenin, promoted nuclear β-catenin accumulation, inhibited mineralization and altered the subcellular localization of E-cadherin in ALCs. Overexpression of PPARγ partially reversed the above results in Per2-knockdown ALCs. Furthermore, in in vivo experiments, the length of incisor eruption was significantly decreased in the circadian disturbance group compared to that in the control group, which was rescued by using a PPARγ agonist in circadian disturbance mice. In conclusion, through regulation of the PPARγ/AKT1/β-catenin signalling axis, PER2 played roles in amelogenin expression, cell junctions and arrangement, enamel matrix secretion and mineralization during ameloblast differentiation, which exert effects on enamel formation.
| S-EPMC8134554 | biostudies-literature
Project description:Nonalcoholic fatty liver disease (NAFLD) is prevalent worldwide; about 25% of NAFLD silently progress into steatohepatitis, in which some of them may develop into fibrosis, cirrhosis and liver failure. However, few drugs are available for NAFLD, partly because of an incomplete understanding of its pathogenic mechanisms. Here, using in vivo and in vitro gain- and loss-of-function approaches, we identified up-regulated DKK1 plays a pivotal role in high-fat diet-induced NAFLD and its progression. Mechanistic analysis reveals that DKK1 enhances the capacity of hepatocytes to uptake fatty acids through the ERK-PPARγ-CD36 axis. Moreover, DKK1 increased insulin resistance by activating the JNK signaling, which in turn exacerbates disorders of hepatic lipid metabolism. Our finding suggests that DKK1 may be a potential therapeutic and diagnosis candidate for NAFLD and metabolic disorder progression.
| S-EPMC9679335 | biostudies-literature
Project description:Background & aimsThe liver is the major organ for metabolizing lipids, and malfunction of the liver leads to various diseases. Nonalcoholic fatty liver disease is rapidly becoming a major health concern worldwide and is characterized by abnormal retention of excess lipids in the liver. CCCTC-binding factor (CTCF) is a highly conserved zinc finger protein that regulates higher-order chromatin organization and is involved in various gene regulation processes. Here, we sought to determine the physiological role of CTCF in hepatic lipid metabolism.MethodsWe generated liver-specific, CTCF-ablated and/or CD36 whole-body knockout mice. Overexpression or knockdown of peroxisome proliferator-activated receptor (PPAR)γ in the liver was achieved using adenovirus. Mice were examined for development of hepatic steatosis and inflammation. RNA sequencing was performed to identify genes affected by CTCF depletion. Genome-wide occupancy of H3K27 acetylation, PPARγ, and CTCF were analyzed by chromatin immunoprecipitation sequencing. Genome-wide chromatin interactions were analyzed by in situ Hi-C.ResultsLiver-specific, CTCF-deficient mice developed hepatic steatosis and inflammation when fed a standard chow diet. Global analysis of the transcriptome and enhancer landscape revealed that CTCF-depleted liver showed enhanced accumulation of PPARγ in the nucleus, which leads to increased expression of its downstream target genes, including fat storage-related gene CD36, which is involved in the lipid metabolic process. Hepatic steatosis developed in liver-specific, CTCF-deficient mice was ameliorated by repression of PPARγ via pharmacologic blockade or adenovirus-mediated knockdown, but hardly rescued by additional knockout of CD36.ConclusionsOur data indicate that liver-specific deletion of CTCF leads to hepatosteatosis through augmented PPARγ DNA-binding activity, which up-regulates its downstream target genes associated with the lipid metabolic process.
| S-EPMC8551791 | biostudies-literature
Project description:UDP-glucuronosyltransferase 1A1 (UGT1A1) is an essential enzyme in mammals that is responsible for detoxification and metabolic clearance of the endogenous toxin bilirubin and a variety of xenobiotics, including some crucial therapeutic drugs. Discovery of potent and safe UGT1A1 inducers will provide an alternative therapy for ameliorating hyperbilirubinaemia and drug-induced hepatoxicity. This study aims to find efficacious UGT1A1 inducer(s) from natural flavonoids, and to reveal the mechanism involved in up-regulating of this key conjugative enzyme by the flavonoid(s) with strong UGT1A1 induction activity. Among all the tested flavonoids, neobavaisoflavone (NBIF) displayed the most potent UGT1A1 induction activity, while its inductive effects were confirmed by both western blot and glucuronidation activity assays. A panel of nuclear receptor reporter assays demonstrated that NBIF activated PPARα and PPARγ in a dose-dependent manner. Meanwhile, we also found that NBIF could up-regulate the expression of PPARα and PPARγ in hepatic cells, suggesting that the induction of UGT1A1 by NBIF was mainly mediated by PPARs. In silico simulations showed that NBIF could stably bind on pocket II of PPARα and PPARγ. Collectively, our results demonstrated that NBIF is a natural inducer of UGT1A1, while this agent induced UGT1A1 mainly via activating and up-regulating PPARα and PPARγ. These findings suggested that NBIF can be used as a promising lead compound for the development of more efficacious UGT1A1 inducers to treat hyperbilirubinaemia and UGT1A1-associated drug toxicities.
| S-EPMC7897654 | biostudies-literature
Project description:With the improvement of people's living standards and lifestyle changes, nonalcoholic fatty liver disease (NAFLD) has become one of the most common chronic liver diseases worldwide. However, few drugs are available for NAFLD, partly due to an incomplete understanding of its pathogenic mechanisms. Here, using in vivo and in vitro gain- and loss-of function approaches, we identified DKK1 as a pivotal mediator of the progression of NAFLD and its accompanying metabolic disorders in dietary obese mice. Mechanistic study reveals that DKK1 enhances the capacity of hepatocytes to uptake fatty acids through ERK-PPARγ-CD36 pathway. Moreover, DKK1 increased insulin resistance by activating the JNK signaling pathway, which in turn exacerbates disorders of hepatic lipid metabolism. These results suggest that DKK1 is a regulator of fatty acid uptake in lipid metabolism and insulin signaling, and may be a potential therapeutic candidate for NAFLD
2022-11-19 | GSE197746 | GEO
Project description:Mycotoxin ochratoxin A (OTA) frequently contaminates various food and feed products, including cereals, coffee and wine. While the nephrotoxicity and teratogenicity of OTA have been extensively documented, the molecular mechanisms associated with OTA toxicity remained poorly understood in a developing organism. We showed that zebrafish embryos exposed to OTA demonstrated incorrect heart looping and small heart chambers. OTA also impaired the renal morphology and reduced the glomerular filtration rate of the embryonic zebrafish. The treatment of embryos with OTA attenuated the expression of the prolactin receptor, a gene (PRLRa) that has a key role in organogenesis and osmoregulation in vertebrates. OTA not only inhibited the phosphorylation of STAT5 and AKT, but also down-regulated the level of serpina1 mRNA in a dose-dependent manner. On the other hand, the microRNA profiling based on RNA sequencing revealed the up-regulation of microRNA-731 (miR-731) in the OTA-treated embryos. Further in silico analysis predicted that PRLRa was a target gene of miR-731. AntagomiR-731 restored PRLRa levels that had been reduced by OTA and also recovered the pronephros morphology that was damaged by OTA. These observations suggest that the exposure to OTA adversely affected the organogenesis of zebrafish, and the modulation of miR-731 and the PRLR signaling cascade contributed to the abnormal renal development mediated by OTA.
| S-EPMC6062247 | biostudies-literature
Project description:The Krüppel-like factor (KLF) family of transcription factors regulates diverse biological processes that include proliferation, differentiation, apoptosis, development, and responses to external stress. In the present study, we aim to investigate the roles of KLF2 in hepatic steatosis. Our results showed that mRNA and protein levels of KLF2 were significantly elevated in livers from obese mice. Adenoviruses-mediated overexpression of KLF2 induced accumulation of triglycerides in C57BL/6 mice, whereas KLF2 silencing ameliorates hepatosteatosis in ob/ob mice. At the molecular level, our data established CD36 as a novel transcriptional target of KLF2. KLF2 upregulated CD36 expression through a consensus binding site on its proximal promoter region. Additionally, the steatotic effect of KLF2 was dramatically inhibited in CD36-null mice. Therefore, our study reveals a novel link between KLF2-induced hepatic triglyceride accumulation and the expression of CD36.
| S-EPMC3927469 | biostudies-literature