Lipid-induced oxidative stress causes steatohepatitis in mice fed an atherogenic diet

Matsuzawa, Naoto; Takamura, Toshinari; Kurita, Seiichiro; Makino, Hírofumi; Ota, Tsuguhito; Ando, Hitoshi; Yokoyama, Masayoshi; Honda, Masao; Zen, Yoh; Nakanuma, Yasuni; Miyamoto, Ken‐ichi

doi:10.1002/hep.21874

Cited by 466 publications

(462 citation statements)

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“…Our initial hypothesis was that ezetimibe treatment ameliorates liver pathology by inhibiting the absorption of toxic lipids such as oxidised cholesterol and palmitate. In our animal model, cholesterol feeding to mice increased not only cholesterol but also triacylglycerols in the liver, and upregulated the gene for sterol regulatory element binding protein (SREBP)-1c that governs fatty acid synthesis [3], probably via activation of liver-X-receptor (LXR) in the liver [25]. Therefore, in experimental models of high-cholesteroldiet-induced steatohepatitis, ezetimibe ameliorated liver steatosis by reducing cholesterol-induced activation of LXR and SREBP-1c [26,27].…”

Section: Discussionmentioning

confidence: 93%

“…Experimentally, palmitate induces interleukin-8 [32], endoplasmic reticulum stress, and c-Jun amino-terminal kinase activation and promotes apoptosis in the liver [5,33,34]. Lipid-induced oxidative stress and inflammation are closely related to insulin resistance [3,5], which could be relevant to the ezetimibe-induced deterioration of glucose homeostasis. Indeed, urinary excretion of 8-isoprostanes was significantly increased in the ezetimibe group compared with the control, and showed significant negative correlation with insulin sensitivity indices such as the Matsuda index and QUICKI in the present study (ESM Table 6).…”

Section: Discussionmentioning

confidence: 99%

“…Steatosis of the liver is closely associated with insulin resistance. However, the toxic lipids are not intrahepatic triacylglycerols but, rather, it is non-esterified cholesterol [3,4] and some NEFA [5] that contribute to inflammation and insulin resistance in hepatocytes.…”

Section: Introductionmentioning

confidence: 99%

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The effects of ezetimibe on non-alcoholic fatty liver disease and glucose metabolism: a randomised controlled trial

et al. 2014

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Aims/hypothesis The cholesterol absorption inhibitor ezetimibe has been shown to ameliorate non-alcoholic fatty liver disease (NAFLD) pathology in a single-armed clinical study and in experimental animal models. In this study, we investigated the efficacy of ezetimibe on NAFLD pathology in an open-label randomised controlled clinical trial. Methods We had planned to enrol 80 patients in the trial, as we had estimated that, with this sample size, the study would have 90% power. The study intervention and enrolment were discontinued because of the higher proportion of adverse events (significant elevation in HbA 1c ) in the ezetimibe group than in the control group. Thirty-two patients with NAFLD were enrolled and randomised (allocation by computer program). Ezetimibe (10 mg/day) was given to 17 patients with NAFLD for 6 months. The primary endpoint was change in serum aminotransferase level. Secondary outcomes were change in liver histology (12 control and 16 ezetimibe patients), insulin sensitivity including a hyperinsulinaemic-euglycaemic clamp study (ten control and 13 ezetimibe patients) and hepatic fatty acid composition (six control and nine ezetimibe patients). Hepatic gene expression profiling was completed in 15 patients using an Affymetrix gene chip. Patients and the physician in charge knew to which group the patient had been allocated, but people carrying out measurements or examinations were blinded to group. Results Serum total cholesterol was significantly decreased in the ezetimibe group. The fibrosis stage and ballooning score were also significantly improved with ezetimibe treatment. However, ezetimibe treatment significantly increased HbA 1c and was associated with a significant increase in hepatic longchain fatty acids. Hepatic gene expression analysis showed coordinate downregulation of genes involved in skeletal muscle development and cell adhesion molecules in the ezetimibe treatment group, suggesting a suppression of stellate cell development into myofibroblasts. Genes involved in the L-carnitine pathway were coordinately downregulated by ezetimibe treatment and those in the steroid metabolism pathway upregulated, suggestive of impaired oxidation of long-chain fatty acids. Conclusions/interpretation Ezetimibe improved hepatic fibrosis but increased hepatic long-chain fatty acids and HbA 1c in patients with NAFLD. These findings shed light on previously unrecognised actions of ezetimibe that should be examined further in future studies.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

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The effects of ezetimibe on non-alcoholic fatty liver disease and glucose metabolism: a randomised controlled trial

et al. 2014

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“…In 2007 Matsuzawa et al described another dietary model for NASH, which closely resembles human NASH (Matsuzawa et al, 2007). This model uses an atherogenic diet, the so-called Paigen-diet containing 15% cocoa butter, 1.25% cholesterol and 0.5% sodium cholate, which was originally created by Beverly…”

Section: I42 Models For Non-alcoholic Steatohepatitis (Nash)mentioning

confidence: 99%

“…Mice were fed standard chow (Ssniff® R/M-H Cat.# V1534-0) or an NASH inducing diet (NASH model) which was also prepared by Ssniff (Soest, Germany) and contains 17% fat, supplemented with 1.25% cholesterol and 0.5% cholate, according to Matsuzawa et al (Matsuzawa et al, 2007 Surgery, University of Regensburg, Germany) using a modified two-step EGTA/ collagenase perfusion procedure (Hellerbrand et al, 2008,Ryan et al, 1993,Weiss et al, 2002. Further, HSC were isolated on a regular basis within our working group from 8-12…”

Section: Ii12 Animalsmentioning

confidence: 99%

The Role of PI3K p110gamma in chronic liver injury

Dostert¹,

Saugspier²,

Dorn³

et al. 2012

Z Gastroenterol

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MASH as an emerging cause of hepatocellular carcinoma: current knowledge and future perspectives

Karin,

Kim

2024

Molecular Oncology

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Hepatocellular carcinoma is one of the deadliest and fastest‐growing cancers. Among HCC etiologies, metabolic dysfunction‐associated fatty liver disease (MAFLD) has served as a major HCC driver due to its great potential for increasing cirrhosis. The obesogenic environment fosters a positive energy balance and results in a continuous rise of obesity and metabolic syndrome. However, it is difficult to understand how metabolic complications lead to the poor prognosis of liver diseases and which molecular mechanisms are underpinning MAFLD‐driven HCC development. Thus, suitable preclinical models that recapitulate human etiologies are essentially required. Numerous preclinical models have been created but not many mimicked anthropometric measures and the course of disease progression shown in the patients. Here we review the literature on adipose tissues, liver‐related HCC etiologies and recently discovered genetic mutation signatures found in MAFLD‐driven HCC patients. We also critically review current rodent models suggested for MAFLD‐driven HCC study.

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Lipid-induced oxidative stress causes steatohepatitis in mice fed an atherogenic diet

Cited by 466 publications

References 49 publications

The effects of ezetimibe on non-alcoholic fatty liver disease and glucose metabolism: a randomised controlled trial

The effects of ezetimibe on non-alcoholic fatty liver disease and glucose metabolism: a randomised controlled trial

The Role of PI3K p110gamma in chronic liver injury

MASH as an emerging cause of hepatocellular carcinoma: current knowledge and future perspectives

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