Identification of cytochrome CYP2E1 as critical mediator of synergistic effects of alcohol and cellular lipid accumulation in hepatocytes in vitro

Mahli, A; Thasler, WE; Patsenker, E.; Müller, Sigrid; Stickel, Felix; Müller, Mike F.; Seitz, HK; Ai, Cederbaum; Hellerbrand, Claus

doi:10.1055/s-0035-1568037

Cited by 4 publications

(5 citation statements)

References 44 publications

(66 reference statements)

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“…Furthermore, increased CYP2E1 and CYP4A11 expression and concomitant exposure to their substrate drugs can lead to severe cellular injury due to the over-production of toxic metabolites, such as acetone from CYP2E1 and ketone bodies from CYP4A11 [20,21]. These findings support that CYP2E1 induces fatty liver disease whether it is induced by alcohol, or not [22,23]. Previous investigations have demonstrated a relationship between NAFLD progression and decreased activity of CYP1A2, CYP2D6, and CYP3A4 [18,24].…”

Section: Discussionmentioning

confidence: 58%

Cytochrome P450 expression-associated multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD) in HepG2 cells

Sukkasem¹,

Chatuphonprasert²,

Jarukamjorn³

2020

Trop. J. Pharm Res

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Purpose: To establish a free fatty acid (FFA)-induced non-alcoholic fatty liver disease (NAFLD) model in HepG2 cells.Methods: HepG2 cells were incubated with 0.1, 1, or 5 mM oleic acid (OA) or palmitic acid (PA) for 24 h. Histological features were examined by oil-red-O staining. Expression levels of metabolic genes (peroxisome proliferator activated receptors α/γ, sterol regulatory element binding proteins 1a/1c, acetyl-CoA carboxylase, acyl-CoA oxidase, and fatty acid synthase), antioxidative genes (catalase and superoxide dismutases 1/2), and cytochrome P450 genes (CYP1A2, CYP2C19, CYP2D6, CYP2E1, CYP3A4, and CYP4A11) were determined by reverse transcription-real time polymerase chain reaction (RT-qPCR).Results: Intracellular lipid storage was observed in cells treated with 1 mM OA or PA while cell shrinkage was present at 5 mM concentrations of both. Expression of all metabolic genes were elevated by 1 mM PA and 5 mM OA and PA. Expression of all antioxidative genes were diminished by 5 mM OA whereas 5 mM PA only reduced superoxide dismutase-2 expression. Expression of CYP1A2, CYP2D6, and CYP3A4 genes were down-regulated by both FFAs, CYP2C19 was induced by PA, while CYP2E1 and CYP4A11 were up-regulated in a concentration-dependent manner.Conclusion: PA was the more potent steatogenic agent in an OA- or PA- induced NAFLD model in HepG2 cells. Increase in intracellular hepatic lipid and expression of metabolic genes, suppression of antioxidative genes, suppression of CYP1A2, CYP2D6, and CYP3A4, and induction of CYP2E1 andCYP4A11 correlated with the multiple-hit pathogenesis model of NAFLD. These findings suggest that PA-induced NAFLD model in HepG2 cells is a suitable in vitro model for studying novel therapeutic approaches to NAFLD treatment. Keywords: NAFLD, Multiple-hit pathogenesis, Free fatty acid, Oleic acid, Palmitic acid

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Section: Discussionmentioning

confidence: 58%

Cytochrome P450 expression-associated multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD) in HepG2 cells

Sukkasem¹,

Chatuphonprasert²,

Jarukamjorn³

2020

Trop. J. Pharm Res

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“…Notably, alcohol and cellular steatosis also induced autophagy in a synergistic manner in hepatocytes in vitro, and this was also mediated via CYP2E1 [32] . Further induction of autophagy ameliorated the joint effects of alcohol and oleic acid on hepatocellular lipid accumulation and inflammatory gene expression while inhibition of autophagy further enhanced the dual pathological effects.…”

Section: An In Vitro Model Of Combined Effects Of Alcohol and Free Famentioning

confidence: 96%

“…More recently, we have developed an in vitro model to study the combined effects of alcohol and FFA on primary human hepatocytes [32] . To induce intracellular lipid accumulation, cells were incubated with FFA complexed to albumin [33] .…”

Section: An In Vitro Model Of Combined Effects Of Alcohol and Free Famentioning

confidence: 99%

Alcohol and Obesity: A Dangerous Association for Fatty Liver Disease

Mahli

Hellerbrand²

2016

Dig Dis

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Alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are the most frequent chronic liver disorders, and their advanced forms - alcoholic steatohepatitis and nonalcoholic steatohepatitis - are the most frequent conditions leading to liver cirrhosis and hepatocellular carcinoma worldwide. NAFLD is considered as the hepatic manifestation of the metabolic syndrome. With the pandemic rise of obesity, the incidence of NAFLD is also further increasing, and considering the life style in modern societies, there is a significant overlap of (risk factors causing) NAFLD and (alcohol consumption predisposing for) ALD at least in Western countries. Epidemiological studies propose a causative link between chronic alcohol consumption and progressive liver disease in obese individuals. Furthermore, experimental studies indicate combined pathological effects of alcohol and obesity or fatty acid levels, respectively, on hepatocellular lipid accumulation and injury as well as hepatic inflammation, fibrosis and cancerogenesis. Notably, these combined pathological effects are in part additive but partly even synergistic. And importantly, alcohol does already exhibit synergistic pathological effects with obesity at moderate doses. This indicates significant differences in the dose threshold for hepatotoxic alcohol effects in lean and obese subjects and herewith also has important implications for recommendations for ‘safe' alcohol consumption. The purpose of this brief review is to update the knowledge on the combined effects of alcohol and obesity on the development and progression of liver disease. Undoubtedly, alcohol and the metabolic syndrome appear as a dangerous mix, and there are important interactive effects of either condition with regard to crucial triggers of liver injury.

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“…Durch CYP2E1 entstandene ROS fördern die alkoholische Fettleber [109,114] durch Hemmung der Fettsäureoxidation über eine mangelnde PPARa-Hochregulierung [109]. Darüber hinaus können auch hepatische Fettsäuren CYP2E1 induzieren und ROS bilden.…”

Section: Verhinderung Von Oxidativem Stress Und Cytochrom P4502e1-indunclassified

Etablierte Therapien und neue therapeutische Ansätze bei der alkoholischen Leberkrankung

Seitz¹,

Mueller²

2016

Z Gastroenterol

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Chronical alcohol abuse causes more than 200 diseases and/or symptoms and among these alcoholic liver disease (ALD) is of special importance since it occurs frequently and may be life-threatening. In Europe alcohol consumption as well as ALD increased as compared to the rest of the world. It has been estimated that in Europe approximately 500 000 people die every year due to ALD. ALD consists of alcoholic fatty liver, alcoholic steatohepatitis (ASH), alcoholic cirrhosis and hepatocellar cancer (HCC ). Alcohol hepatitis (AH) is a clinical feature with jaundice and liver failure and a high mortality. The course of ALD is variable and depends among others, on genetics, gender, the presence of other liver diseases as well as exposure towards toxic substances and drugs. The treatment of ALD mainly consists of alcohol abstinence which may be difficult to achieve in the alcoholic. The results of the therapy improve by cognitive psychotherapy as well as antigraving medication. The treatment of AH with poor prognosis is limited. Although a number of therapeutic approaches in AH have been tried, the present therapy consists of intensive care in association with the administration of steroids, hyperalimentation and possibly the administration of N-acetylcystein. Presently it is discussed whether liver transplantation is an option for these patients. New therapeutic approaches focuses on pathopyhsiologically identified targets in ALD. This includes elimination of endotoxines, cytokines, and chemokines as well as an inhibition oxidative stress. Antigraving substances, such as Nalmafen also may improve liver function since their administration degreases alcohol consumption. In addition, betain to stimulate methyltransfer as well the inhibition of apoptosis have been investigated. Stimulation of liver regeneration by granulozytecolony stimulating factor as well as mesenchymalcell and bone marrow transplantation have shown some positive results. Nevertheless new therapeutic strategies are urgently needed. Especially in AH with its high mortality.

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Identification of cytochrome CYP2E1 as critical mediator of synergistic effects of alcohol and cellular lipid accumulation in hepatocytes in vitro

Cited by 4 publications

References 44 publications

Cytochrome P450 expression-associated multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD) in HepG2 cells

Cytochrome P450 expression-associated multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD) in HepG2 cells

Alcohol and Obesity: A Dangerous Association for Fatty Liver Disease

Etablierte Therapien und neue therapeutische Ansätze bei der alkoholischen Leberkrankung

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