A High-Cholesterol Diet Exacerbates Liver Fibrosis in Mice via Accumulation of Free Cholesterol in Hepatic Stellate Cells

Teratani, Toshiaki; Tomita, Kengo; Suzuki, Takahiro; Oshikawa, Tetsuya; Yokoyama, Hirokazu; Shimamura, Katsuyoshi; Tominaga, Susumu; Hiroi, Sadayuki; Irie, Rie; Okada, Yoshikiyo; Kurihara, Chie; Ebinuma, Hirotoshi; Saito, Hidetsugu; Hokari, Ryota; Sugiyama, Kazuo; Kanai, Takanori; Miura, Soichiro; Hibi, Toshifumi

doi:10.1053/j.gastro.2011.09.049

Cited by 190 publications

(171 citation statements)

References 22 publications

Supporting

Mentioning

161

Contrasting

Unclassified

Order By: Relevance

“…Controlling hepatic inflammation is an obvious target for NASH therapy. 18 In the current study, by feeding rats a HFHC diet for 12 weeks, significant increase in body weight, liver weight and serum ALT and AST levels were detected suggesting the development of NASH model in rats which was confirmed by the histopathological findings such as steatosis, ballooning degeneration and lobular inflammation. These findings are in accordance with previous researches.…”

Section: Discussionsupporting

confidence: 73%

Beneficial effects of diacerein on adipokines and pro-inflammatory cytokines involved in diet-induced nonalcoholic steatohepatitis in rats

Allah

2017

Int J Basic Clin Pharmacol

View full text Add to dashboard Cite

Background: Non-alcoholic steatohepatitis (NASH) is considered as a progressive liver disease, so effective therapies are needed to ameliorate hepatic steatosis, inflammation and fibrosis, and to prevent the progression to cirrhosis and hepatocellular carcinoma. Diacerein is an anti-inflammatory drug that inhibits the synthesis and activity of pro-inflammatory cytokines. The present study was designed to investigate the effect of diacerein on pro-inflammatory cytokines as well as adipokines involved in diet-induced NASH rat model.Methods: Thirty-two adult male rats were divided into four groups: control, diacerein-treated, NASH-untreated and NASH+diacerein-treated groups. NASH was induced by feeding rats with high-fat and high-cholesterol diet for 12 weeks. Body weight, liver weight, fasting blood glucose and insulin levels for estimation of insulin resistance, blood lipids, alanine transaminase, and aspartate aminotransferase were evaluated. Serum levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), adiponectin, visfatin and leptin were also detected. Histopathological examination of liver sections was performed.Results: Diacerein significantly reduced liver weight, fasting blood glucose, insulin level, transaminases and ameliorates insulin resistance with favourable effects on blood lipids. These results were accompanied with a significant reduction in serum levels of TNF-α, IL-1β, IL-6, and visfatin, while, adiponectin was significantly increased and leptin was insignificantly affected. Liver sections revealed that diacerein reduced steatosis and lobular inflammatory grades.Conclusions: These data suggest that diacerein administration may have a potential usefulness in the prevention of NASH as a possible result of inhibition of pro-inflammatory cytokines and the beneficial effects on adipokines especially adiponectin and visfatin.

show abstract

Section: Discussionsupporting

confidence: 73%

Beneficial effects of diacerein on adipokines and pro-inflammatory cytokines involved in diet-induced nonalcoholic steatohepatitis in rats

Allah

2017

Int J Basic Clin Pharmacol

View full text Add to dashboard Cite

show abstract

“…Hepatic stellate cells, in particular, are responsible for liver fibrosis in NASH. It has recently been reported that intracellular cholesterol accumulation directly activates hepatic stellated cells through a toll-like receptor-4-dependent pathway and triggers hepatic fibrosis [29]. These effects might be more evident in humans because, unlike rodents, where NPC1L1 is primarily expressed in the intestine, in humans NPC1L1 mRNA is highly expressed both in the small intestine and liver.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2014

View full text Add to dashboard Cite

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.

show abstract

“…Lipotoxicity involving these lipids is commonly found in metabolic syndrome, insulin resistance, and type 2 diabetes ( 7 ), which are frequent comorbidities associated with NAFLD ( 8,9 ). Further, while the role of lipids in fi brosis is often discussed in the context of repair ( 10 ), their ability to regulate oxidative stress and key transcription factors appears more infl uential and may have signifi cant effects on the progression of NAFLD ( 11,12 ). Lipids are also important mediators of infl ammatory signals, and previous studies have yielded information about plasma and liver lipids in the setting of NASH.…”

Section: Methodsmentioning

confidence: 99%

Biomarkers of NAFLD progression: a lipidomics approach to an epidemic

Gorden

Myers

Ivanova

et al. 2015

Journal of Lipid Research

287

266

View full text Add to dashboard Cite

Nonalcoholic fatty liver disease (NAFLD) is rapidly becoming one of the most common forms of liver disease in Abstract The spectrum of nonalcoholic fatty liver disease (NAFLD) includes steatosis, nonalcoholic steatohepatitis (NASH), and cirrhosis. Recognition and timely diagnosis of these different stages, particularly NASH, is important for both potential reversibility and limitation of complications. Liver biopsy remains the clinical standard for defi nitive diagnosis. Diagnostic tools minimizing the need for invasive procedures or that add information to histologic data are important in novel management strategies for the growing epidemic of NAFLD. We describe an "omics" approach to detecting a reproducible signature of lipid metabolites, aqueous intracellular metabolites, SNPs, and mRNA transcripts in a double-blinded study of patients with different stages of NAFLD that involves profi ling liver biopsies, plasma, and urine samples. Using linear discriminant analysis, a panel of 20 plasma metabolites that includes glycerophospholipids, sphingolipids, sterols, and various aqueous small molecular weight components involved in cellular metabolic pathways, can be used to differentiate between NASH and steatosis. This identifi cation of differential biomolecular signatures has the potential to improve clinical diagnosis and facilitate therapeutic intervention of

show abstract

A High-Cholesterol Diet Exacerbates Liver Fibrosis in Mice via Accumulation of Free Cholesterol in Hepatic Stellate Cells

Cited by 190 publications

References 22 publications

Beneficial effects of diacerein on adipokines and pro-inflammatory cytokines involved in diet-induced nonalcoholic steatohepatitis in rats

Beneficial effects of diacerein on adipokines and pro-inflammatory cytokines involved in diet-induced nonalcoholic steatohepatitis in rats

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

Biomarkers of NAFLD progression: a lipidomics approach to an epidemic

Contact Info

Product

Resources

About