Nuciferine downregulates Per-Arnt-Sim kinase expression during its alleviation of lipogenesis and inflammation on oleic acid-induced hepatic steatosis in HepG2 cells

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Abstract

Non-alcoholic fatty liver disease (NAFLD) is a prevalent liver disease associated with lipotoxicity, lipid peroxidation, oxidative stress, and inflammation. Nuciferine, an active ingredient extracted from the natural lotus leaf, has been reported to be effective for the prevention and treatment of NAFLD. Per-Arnt-Sim kinase (PASK) is a nutrient responsive protein kinase that regulates lipid and glucose metabolism, mitochondrial respiration, and gene expression. The aim of the present study was to investigate the protective effect of nuciferine against NAFLD and its inhibitory effect on PASK, exploring the possible underlying mechanism of nuciferine-mediated inhibition on NAFLD. Relevant biochemical parameters (lipid accumulation, extent of oxidative stress and release of inflammation cytokines) in oleic acid (OA)-induced HepG ₂ cells that mimicked steatosis in vitro were measured and compared with the control. It was found that nuciferine and silenced-PASK (siRNA PASK) both inhibited triglyceride (TG) accumulation and was effective in decreasing fatty acid (FFAs). The content of total antioxidant capacity (T-AOC) and superoxide dismutase (SOD) were increased respectively by nuciferine and siRNA PASK without increase in glutathione (GSH). Malondialdehyde (MDA) was decreased respectively by nuciferine and siRNA PASK. In addition, nuciferine decreased TNF-a, IL-6 and IL-8 as well as the siRNA PASK group. IL-10 was increased by nuciferine and siRNA PASK respectively. Further investigation revealed that nuciferine and siRNA PASK could respectively regulate the expression of target genes involved in lipogenesis and inflammation, suggesting that nuciferine may be a potential therapeutic treatment for NAFLD. Furthermore, the modulated effect of nuciferine on (OA)-induced HepG ₂ cells lipogenesis and inflammation, which was accompanied with PASK inhibition, was also consistent with siRNA PASK, implying that PASK might play a role in nuciferine-mediated regulation on NAFLD.

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Most cited references 36

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Epidemiology of Non-Alcoholic Fatty Liver Disease

Stefano Bellentani, Federica Scaglioni, Mariano Marino … (2010)

Non-alcoholic fatty liver disease (NAFLD) is rapidly becoming the most common liver disease worldwide. The prevalence of NAFLD in the general population of Western countries is 20–30%. About 2–3% of the general population is estimated to have non-alcoholic steatohepatitis (NASH), which may progress to liver cirrhosis and hepatocarcinoma. As a rule, the prevalence of NAFLD is higher in males and increases with increasing age, and it is influenced by the diagnostic method and the characteristics of the population, especially lifestyle habits. Population-based studies provide better estimates of the prevalence of NAFLD as compared to autoptic and clinical studies, but few such studies have been performed to date. The diagnosis of NAFLD in population studies is usually obtained by ultrasonography, which is known to underestimate the prevalence of fatty liver. The Dallas Heart Study and the Dionysos Study reported that 30% of the adults in the USA and 25% in Italy have NAFLD. In these studies, 79% and 55% of patients with NAFLD had normal aminotransferase levels, showing that liver enzymes are not surrogate markers of NAFLD in the general population. Noninvasive markers such as the fatty liver index obtained from the Dionysos Study may be useful to screen for NAFLD in the general population. The most important risk factors for NAFLD are male gender, age, obesity, insulin resistance and the cardiometabolic alterations that define the metabolic syndrome. The prevalence of NAFLD is 80–90% in obese adults, 30–50% in patients with diabetes and up to 90% in patients with hyperlipidemia. The prevalence of NAFLD among children is 3–10%, rising up to 40–70% among obese children. Moreover, pediatric NAFLD increased from about 3% a decade ago to 5% today, with a male-to-female ratio of 2:1. The incidence and natural history of NAFLD are still not well defined, but it is recognized that the majority of individuals with NAFLD do not develop NASH. The incidence of NAFLD is probably increasing in Western countries, strictly linked to lifestyle habits.

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Increase in long-chain polyunsaturated fatty acid n - 6/n - 3 ratio in relation to hepatic steatosis in patients with non-alcoholic fatty liver disease.

Julia Araya, Ramón Rodrigo, Luis Videla … (2004)

Hepatic steatosis is a major feature associated with NAFLD (non-alcoholic fatty liver disease). The aims of the present study were to assess the levels of PUFA (polyunsaturated fatty acids) in liver total lipids, triacylglycerols (triglycerides) and phospholipids of NAFLD patients in relation to those in adipose tissue and hepatic indexes related to oxidative stress as factors contributing to hepatic steatosis. Eleven control subjects and 19 patients with NAFLD were studied. Analysis of liver and abdominal adipose tissue fatty acids was carried out by GLC. The liver content of protein carbonyl groups and malondialdehyde were taken as indexes related to oxidative stress. NAFLD patients had a depletion in LCPUFA (long-chain PUFA) of the n -6 and n -3 series in liver triacylglycerols, with decreased 20:4, n -6/18:2, n -6 and (20:5, n -3+22:6, n -3)/18:3, n -3 ratios, whereas liver phospholipids contained higher n -6 and lower n -3 LCPUFA. These findings were accompanied by an enhancement of (i) n -6/ n -3 ratio in liver and adipose tissue, (ii) 18:1, n -9 trans levels in adipose tissue, and (iii) hepatic lipid peroxidation and protein oxidation indexes. It is concluded that a marked enhancement in LCPUFA n -6/ n -3 ratio occurs in the liver of NAFLD patients, a condition that may favour lipid synthesis over oxidation and secretion, thereby leading to steatosis. Depletion of hepatic LCPUFA may result from both defective desaturation of PUFA, due to inadequate intake of precursors, such as 18:3, n -3, and higher intake of the 18:1, n -9 trans isomer leading to desaturase inhibition, and from an increased peroxidation of LCPUFA due to oxidative stress.

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Non-alcoholic fatty liver disease: further expression of the metabolic syndrome.

G. Saldalamacchia, Paolo Conca, D A Arena … (2007)

Non-alcoholic fatty liver disease has been associated with metabolic disorders, including central obesity, dyslipidemia, hypertension and hyperglycemia. Metabolic syndrome, obesity, and insulin resistance are major risk factors in the pathogenesis of non-alcoholic fatty liver disease. Non-alcoholic fatty liver disease refers to a wide spectrum of liver damage, ranging from simple steatosis to non-alcoholic steatohepatitis, advanced fibrosis and cirrhosis.

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Author and article information

Contributors

Dan-Dan Zhang: URI : http://loop.frontiersin.org/people/181387/overview

Guan-Hua Zhu: URI : http://loop.frontiersin.org/people/283306/overview

Xiao-Yu Li: URI : http://loop.frontiersin.org/people/268389/overview

Journal

Journal ID (nlm-ta): Front Pharmacol

Journal ID (iso-abbrev): Front Pharmacol

Journal ID (publisher-id): Front. Pharmacol.

Title: Frontiers in Pharmacology

Publisher: Frontiers Media S.A.

ISSN (Electronic): 1663-9812

Publication date (Electronic): 21 October 2015

Publication date Collection: 2015

Volume: 6

Electronic Location Identifier: 238

Affiliations

Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine Shanghai, China

Author notes

Edited by: Giovanni Li Volti, University of Catania, Italy

Reviewed by: Luca Vanella, University of Catania, Italy; Ignazio Barbagallo, University of Catania, Italy

*Correspondence: Xiao-Yu Li, lixiaoyulxb@ 123456163.com

^† These authors have contributed equally to this works.

This article was submitted to Experimental Pharmacology and Drug Discovery, a section of the journal Frontiers in Pharmacology

Article

DOI: 10.3389/fphar.2015.00238

PMC ID: 4612658

PubMed ID: 26539118

SO-VID: 2bbe6757-7738-4f04-8b55-b7d8589fe6ac

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

History

Date received : 28 August 2015

Date accepted : 02 October 2015

Page count

Figures: 9, Tables: 1, Equations: 0, References: 48, Pages: 15, Words: 0

Funding

Funded by: Opening Project of State Key Laboratory of High Performance Ceramics and Superfine Microstructure

Award ID: No.SKL 201306SIC

Funded by: Crossing Program between Medicine and Industry Supported by Shanghai Jiaotong University

Award ID: No.YG2014MS32

Funded by: Research Fund for the Doctoral Programof Higher Education of China

Award ID: No.20110073120097

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Nuciferine downregulates Per-Arnt-Sim kinase expression during its alleviation of lipogenesis and inflammation on oleic acid-induced hepatic steatosis in HepG ₂ cells

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Most cited references 36

Epidemiology of Non-Alcoholic Fatty Liver Disease

Increase in long-chain polyunsaturated fatty acid n - 6/n - 3 ratio in relation to hepatic steatosis in patients with non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease: further expression of the metabolic syndrome.

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Cited by 31

Most referenced authors 486

Nuciferine downregulates Per-Arnt-Sim kinase expression during its alleviation of lipogenesis and inflammation on oleic acid-induced hepatic steatosis in HepG 2 cells

Read this article at

Gamma Delta T cells

Epidemiology of Non-Alcoholic Fatty Liver Disease

Increase in long-chain polyunsaturated fatty acid n - 6/n - 3 ratio in relation to hepatic steatosis in patients with non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease: further expression of the metabolic syndrome.

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Nuciferine downregulates Per-Arnt-Sim kinase expression during its alleviation of lipogenesis and inflammation on oleic acid-induced hepatic steatosis in HepG ₂ cells