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 456 publications

(446 citation statements)

References 49 publications

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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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Neutral ceramidase‐enriched exosomes prevent palmitic acid‐induced insulin resistance in H4IIEC3 hepatocytes

Zhu

Jin

2016

FEBS Open Bio

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Oversupply of free fatty acids such as palmitic acid (PA) from the portal vein may cause liver insulin resistance. Production of reactive oxygen species plays a pivotal role in PA‐induced insulin resistance in H4IIEC3 hepatocytes. Recently, we found that exosomes secreted from INS‐1 cells that were transfected with neutral ceramidase (NCDase) plasmids had raised NCDase activity; these NCDase‐enriched exosomes could inhibit PA‐induced INS‐1 cell apoptosis. Here, we showed that PA reduced insulin‐stimulated tyrosine phosphorylation of insulin receptor substrate 2 and decreased insulin‐stimulated uptake of the fluorescent glucose analog 2‐NBDG, confirming that insulin resistance occurred in PA‐treated H4IIEC3 cells. Moreover, NCDase‐enriched exosomes from INS‐1 cells rescued PA‐induced H4IIEC3 insulin resistance and blocked PA‐induced reactive oxygen species production in which ceramide was involved.

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

Cited by 456 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

Neutral ceramidase‐enriched exosomes prevent palmitic acid‐induced insulin resistance in H4IIEC3 hepatocytes

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