Ezetimibe Increases Hepatic Iron Levels in Mice Fed a High-Fat Diet

Kishino, Yoshinobu; Tanaka, Yuji; Ikeda, Takanori; Yamamoto, Kazuo; Ogawa, Hiroshi; Iwatani, Yoshinori; Kamisako, Toshinori

doi:10.1124/jpet.113.203448

Cited by 6 publications

(6 citation statements)

References 52 publications

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“…Our results demonstrated that insulin therapy effectively released HIO, manifested by the recovery of liver iron content and serum ferritin and the improvement tendency of serum sTfR, and lowered serum iron to normal level in STZ-induced both type 1 and type 2 diabetic rats. In addition, simple HFD induction that led to IR but did not elevate fasting blood glucose had no influence on liver or serum iron, which was not reported in other studies (23,33). These findings suggest that body iron homeostasis may be closely related to insulin signaling.…”

Section: Discussionmentioning

confidence: 42%

“…Insulin supplementation eliminated these abnormal changes in STZ and HFD+STZ rats, indicating that hepcidin, which negatively regulates Fpn and iron absorption and restricts the level of serum iron, may be positively regulated by insulin. It was also found in other HFD rat models that hepcidin expression remained unchanged (33,38) or began decreasing only when fasting blood glucose was increased (39). Clinical studies (16,17,34) showed that the prohepcidin or hepcidin level in blood was significantly decreased in DM2 patients with hyperferritinemia.…”

Section: Discussionmentioning

confidence: 86%

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Hepcidin Is Directly Regulated by Insulin and Plays an Important Role in Iron Overload in Streptozotocin-Induced Diabetic Rats

et al. 2014

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Iron overload is frequently observed in type 2 diabetes mellitus (DM2), but the underlying mechanisms remain unclear. We hypothesize that hepcidin may be directly regulated by insulin and play an important role in iron overload in DM2. We therefore examined the hepatic iron content, serum iron parameters, intestinal iron absorption, and liver hepcidin expression in rats treated with streptozotocin (STZ), which was given alone or after insulin resistance induced by a high-fat diet. The direct effect of insulin on hepcidin and its molecular mechanisms were furthermore determined in vitro in HepG2 cells. STZ administration caused a significant reduction in liver hepcidin level and a marked increase in intestinal iron absorption and serum and hepatic iron content. Insulin obviously upregulated hepcidin expression in HepG2 cells and enhanced signal transducer and activator of transcription 3 protein synthesis and DNA binding activity. The effect of insulin on hepcidin disappeared when the signal transducer and activator of transcription 3 pathway was blocked and could be partially inhibited by U0126. In conclusion, the current study suggests that hepcidin can be directly regulated by insulin, and the suppressed liver hepcidin synthesis may be an important reason for the iron overload in DM2.

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Section: Discussionmentioning

confidence: 42%

Section: Discussionmentioning

confidence: 86%

Hepcidin Is Directly Regulated by Insulin and Plays an Important Role in Iron Overload in Streptozotocin-Induced Diabetic Rats

et al. 2014

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“…Insulin resistance or impaired insulin signaling is a main contributor to the disruption of glucose metabolism and plays a pivotal role in pathogenesis of T2DM ( 47 , 48 ). Reciprocally, the improvement or restoration of insulin signaling is an effective treatment for restoring abnormal glucose metabolism in T2DM ( 49 ). In this study, we found that MARCKS deficiency increased glucose levels in serum and accelerated insulin resistance in HF diet-fed mice.…”

Section: Discussionmentioning

confidence: 99%

Carnosic acid protects mice from high-fat diet-induced NAFLD by regulating MARCKS

Song¹,

Li²,

Liu

et al. 2018

Int J Mol Med

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Non-alcoholic fatty liver disease (NAFLD) comprises a spectrum of liver damage characterized by abnormal hepatic fat accumulation and inflammatory response. Although the molecular mechanisms responsible for the disease are not yet fully understood, the pathogenesis of NAFLD likely involves multiple signals. The identification of effective therapeutic strategies to target these signals is of utmost importance. Carnosic acid (CA), as a phenolic diterpene with anticancer, anti-bacterial, anti-diabetic and neuroprotective properties, is produced by many species of the Lamiaceae family. Myristoylated alanine-rich C-kinase substrate (MARCKS) is a major protein kinase C (PKC) substrate in many different cell types. In the present study, wild-type C57BL/6 and MARCKS-deficient mice were randomly divided into the normal chow- or high-fat (HF) diet-fed groups. The HF diet increased the fasting glucose and insulin levels, and promoted glucose intolerance in the wild-type mice. MARCKS deficiency further upregulated intolerance, fasting glucose and insulin. The HF diet also promoted hepatic steatosis, serum alanine transaminase (ALT) and aspartate transaminase (AST) activity, inflammation and lipid accumulation in the wild-type mice. These responses were accelerated in the MARCKS-deficient mice. Importantly, increased inflammation and lipid accumulation were associated with phosphoinositide 3-kinase (PI3K)/AKT, NLR family pyrin domain containing 3 (NLRP3)/nuclear factor-κB (NF-κB) and sterol regulatory element binding protein-1c (SREBP-1c) signaling pathway activation. The mice treated with CA exhibited a significantly improved glucose and insulin tolerance. The production of pro-inflammatory cytokines and lipid accumulation were suppressed by CA. Significantly, MARCKS was reduced in mice fed the HF diet. CA treatment upregulated MARCKS expression compared to the HF group. Furthermore, the activation of the PI3K/AKT, NLRP3/NF-κB and SREBP-1c signaling pathways was inhibited by CA. Taken together, our data suggest that CA suppresses inflammation and lipogenesis in mice fed a HF diet through MARCKS regulation. Thus, CA may be prove to be a useful anti-NAFLD agent.

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“…Hepatic steatosis, induced by a high-fat diet, but not a high-fructose diet, was inhibited by ezetimibe administration (8). It has also been reported that hepatic iron levels in mice fed a high-fat diet are increased following treatment with ezetimibe (9). Despite these notable findings, mechanisms by which ezetimibe administration ameliorates hepatic steatosis, insulin resistance and obesity remain largely unexplored.…”

Section: Introductionmentioning

confidence: 98%

Ezetimibe prevents the development of non-alcoholic fatty liver disease induced by high-fat diet in C57BL/6J mice

Wang

Ren

et al. 2014

Molecular Medicine Reports

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There is currently no established treatment for non-alcoholic fatty liver disease (NAFLD), including its most extreme form, non-alcoholic steatohepatitis (NASH). Ezetimibe, an inhibitor of Niemann-Pick C1 Like 1-dependent cholesterol absorption, improves diet-induced hyperlipidemia and attenuates liver steatosis and insulin resistance. The aim of the present study was to determine whether ezetimibe treatment is able to inhibit the development of NAFLD, and to elucidate the underlying mechanism, using C57BL/6J (B6) mice maintained on a high-fat diet. Male B6 mice (20 weeks of age) were divided into the following two groups (n=7 in each group): Mice fed a high-fat diet for four weeks and mice fed a high-fat diet with 0.0064% (wt/wt) ezetimibe (5 mg/kg/day) for four weeks. Administration of ezetimibe significantly reduced liver steatosis and fibrosis. Ezetimibe reduced serum cholesterol, hepatic fat accumulation and insulin resistance in the liver of mice fed the high-fat diet. Furthermore, ezetimibe significantly reduced hepatic mRNA expression of Acc1 and Scd1, which are involved in hepatic fatty acid synthesis. Ezetimibe significantly reduced hepatic Cd36 gene expression, upregulation of which is significantly associated with insulin resistance, hyperinsulinemia and increased steatosis. The protein expression of SKP2, a viable therapeutic target in human cancer, was also reduced by ezetimibe. These findings suggest that ezetimibe may be an effective therapy for high fat-induced NAFLD, including NASH.

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Ezetimibe Increases Hepatic Iron Levels in Mice Fed a High-Fat Diet

Cited by 6 publications

References 52 publications

Hepcidin Is Directly Regulated by Insulin and Plays an Important Role in Iron Overload in Streptozotocin-Induced Diabetic Rats

Hepcidin Is Directly Regulated by Insulin and Plays an Important Role in Iron Overload in Streptozotocin-Induced Diabetic Rats

Carnosic acid protects mice from high-fat diet-induced NAFLD by regulating MARCKS

Ezetimibe prevents the development of non-alcoholic fatty liver disease induced by high-fat diet in C57BL/6J mice

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