699 Nateglinide improves non-alcoholic steatohepatitis (NASH) with type 2 diabetes

Beneficial effect of eugenol on fatty liver was examined in hepatocytes and liver tissue of high fat diet (HFD)-fed C57BL/6J mice. To induce a fatty liver, palmitic acid or isolated hepatocytes from HFD-fed Sprague-Dawley (SD) rats were used in vitro studies, and C57BL/6J mice were fed HFD for 10 weeks. Lipid contents were markedly decreased when hepatocytes were treated with eugenol for up to 24 h. Gene expressions of sterol regulatory element binding protein 1 (SREBP1) and its target enzymes were suppressed but those of lipolysis-related proteins were increased. As a regulatory kinase for lipogenic transcriptional factors, the AMP-activated protein kinase (AMPK) signaling pathway was examined. Protein expressions of phosphorylated Ca 2 -calmodulin dependent protein kinase kinase (CAMKK), AMPK and acetyl-CoA carboxylase (ACC) were significantly increased and those of phosphorylated mammalian target of rapamycin (mTOR) and p70S6K were suppressed when the hepatocytes were treated with eugenol at up to 100 µM. These effects were all reversed in the presence of specific inhibitors of CAMKK, AMPK or mTOR. In vivo studies, hepatic triglyceride (TG) levels and steatosis score were decreased by 45% and 72%, respectively, in eugenoltreated mice. Gene expressions of fibrosis marker protein such as α-smooth muscle actin (α-SMA), collagen type I (Col-I) and plasminogen activator inhibitor-1 (PAI-1) were also significantly reduced by 36%, 63% and 40% in eugenol-treated mice. In summary, eugenol may represent a potential intervention in populations at high risk for fatty liver.Key words eugenol; fatty liver; fibrosis; AMP-activated protein kinase; sterol regulatory element binding protein Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver ailment worldwide.1) While hepatic steatosis is often asymptomatic, it can progress to non-alcoholic steatohepatitis (NASH). If untreated, NASH can progress to cirrhosis and increased risk of early mortality.2) Obesity and insulin resistance, as seen in type 2 diabetes mellitus (T2DM), and hypertriglyceridemia are well-documented risk factors for NAFLD.3) These factors are key targets for prevention and therapy of NAFLD tends to focus on addressing the obesity or insulin resistance rather than NAFLD itself. NAFLD in the hepatic steatosis (HS) phase can be reversed by lifestyle modification, while NASH is more difficult to treat. Thus, preventing the progression of HS to NASH is of primary importance. Lifestyle recommendations for NAFLD are generally limited to losing weight through energy restriction and/or increasing physical activity, which is often to fail to hold on to them. With this notion, phytochemicals obtained from medicinal plants or foods are attracting alternative options for the treatment of NAFLD and prevention to progress to NASH.

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“…20) Therefore, there is in great demand for development of effective and safe therapeutics for NAFLD.…”

Section: Discussionmentioning

confidence: 99%

Eugenol Ameliorates Hepatic Steatosis and Fibrosis by Down-Regulating SREBP1 Gene Expression <i>via</i> AMPK-mTOR-p70S6K Signaling Pathway

Kim

Jeong

et al. 2014

Biological & Pharmaceutical Bulletin

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“…51 These approaches, explored in therapy for both adult and pediatric NASH, include (1) diagnosis and treatment of related metabolic disturbances such as diabetes and hyperlipidaemia (2) targeting IR by weight loss (healthy lifestyle: diet and exercise) or pharmacotherapy and (3) control of the secondary processes promoting to oxidative stress, inflammation, apoptosis and hepatic fibrosis by using hepatoprotective agents such as antioxidants. 6,26,[130][131][132][133][134][135][136][137][138][139] However, it is important to exclude secondary causes for hepatic steatosis. Treatment in these cases differs and revolves around correcting the underlying cause.…”

Section: Treatmentmentioning

confidence: 99%

“…130 Table 5 has shown the list of pharmacological agents attributed to the treatment of NAFLD-NASH. [131][132][133][134][135][136][137][138][139][140][141][142][143][144][145][146][147] Only metformin 135 and vitamin E 140 have been used until now in clinical trials, but there is some evidence because of efficacy in adult and safety in children for other groups such as antiobesity (orlistat), 129,131 angiotensin-converting enzyme inhibitor 132 and stations. 133,138 These evidences in parallel to other novel therapies [141][142][143][144][145][146][147] must be considered in designing future clinical trials for treatment of pediatric fatty liver.…”

Section: Treatmentmentioning

confidence: 99%

Nonalcoholic fatty liver disease: a challenge for pediatricians

Widhalm

Ghods

2010

Int J Obes

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Background: Nonalcoholic fatty liver disease (NAFLD) is the most common cause of pediatric liver disease. Its prevalence is related to the growing epidemic in childhood obesity during the past decades. At present, NAFLD and nonalcoholic steatohepatitis (NASH) are increasingly recognized worldwide. In spite of alarming trend in the epidemiology in pediatric field and growing risk of end stage liver disease, there is no significant advance in its diagnosis and treatment. Aim: To provide a detailed review for diagnosis and management of NAFLD and NASH. Methods: By using Pubmed to find review articles and relevant research. Results: The prevalence ranges from at least 3% in children overall to about 50% in obese children. The noninvasive biomarkers can be used to identify NAFLD/NASH patients. Diagnostic criteria based on biochemical and immunological indicators in the high-risk group of children could prevent about half of cases from receiving an invasive test. The pharmacological and surgical interventions have shown a growing role in pediatric NAFLD. Novel treatment modalities, such as probiotics, have hardly been studied. Conclusion: Early diagnosis by using noninvasive screening methods in high-risk groups is the most effective strategy against the NAFLD. The biology of early growth and development, including hepatic metabolism, may hold the key to pediatric NAFLD. Prevention of overweight children and childhood obesity is undoubtedly the best strategy for treating NAFLD.

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“…However, because positive relationship between the expression of PPARα and CPT-1 or ACO was observed in the present study, transcriptional regulation of lipid oxidation pathway by PPARα might play a critical role for the preventive effect of NAT on fatty liver. Morita et al [27] reported that 16 weeks of treatment with NAT led to improvement of histologic changes in the livers of nonalcoholic fatty liver disease (nonalcoholic steatohepatitis) patients. Therefore, although the mechanism by which NAT regulates hepatic expression of PPARα remains unclear, it might be a potential agent for use in the prevention of fatty liver disease, such as nonalcoholic steatohepatitis.…”

Section: Discussionmentioning

confidence: 99%

Nateglinide prevents fatty liver through up-regulation of lipid oxidation pathway in Goto-Kakizaki rats on a high-fat diet

et al. 2008

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699 Nateglinide improves non-alcoholic steatohepatitis (NASH) with type 2 diabetes

Cited by 28 publications

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Eugenol Ameliorates Hepatic Steatosis and Fibrosis by Down-Regulating SREBP1 Gene Expression <i>via</i> AMPK-mTOR-p70S6K Signaling Pathway

Eugenol Ameliorates Hepatic Steatosis and Fibrosis by Down-Regulating SREBP1 Gene Expression <i>via</i> AMPK-mTOR-p70S6K Signaling Pathway

Nonalcoholic fatty liver disease: a challenge for pediatricians

Nateglinide prevents fatty liver through up-regulation of lipid oxidation pathway in Goto-Kakizaki rats on a high-fat diet

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