Cytochrome P450 2E1‐dependent hepatic ethanol metabolism induces fatty acid‐binding protein 4 and steatosis

Attal, Neha; Marrero, Emilio; Thompson, Kyle J.; McKillop, Iain H.

doi:10.1111/acer.14828

Cited by 7 publications

(9 citation statements)

References 52 publications

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“…PPARα is a ligand-activated transcription factor abundantly expressed in the liver. PPARα activators are reported to prevent acetaminophen-induced hepatotoxicity, which involves regulation of lipid metabolism and inhibition of CYP2E1 activity ( Attal et al, 2022 ). In two previous studies, 2-hydroxyacyl-CoA lyase levels significantly decreased while proteins associated with PPAR signaling, peroxisome proliferation, and omega oxidation, specifically CYP4A10 and CYP4A14, significantly increased in the liver proteome ( Mezzar et al, 2017 ; Khalil et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

Inflammatory signaling on cytochrome P450-mediated drug metabolism in hepatocytes

Wang

Rao²,

Tan³

et al. 2022

Front. Pharmacol.

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Cytochrome P450 (CYP450) enzymes are membrane-bound blood proteins that are vital to drug detoxification, cell metabolism, and homeostasis. CYP450s belonging to CYP families 1–3 are responsible for nearly 80% of oxidative metabolism and complete elimination of approximately 50% of all common clinical drugs in humans liver hepatocytes. CYP450s can affect the body’s response to drugs by altering the reaction, safety, bioavailability, and toxicity. They can also regulate metabolic organs and the body’s local action sites to produce drug resistance through altered drug metabolism. Genetic polymorphisms in the CYP gene alone do not explain ethnic and individual differences in drug efficacy in the context of complex diseases. The purpose of this review is to summarize the impact of new inflammatory-response signaling pathways on the activity and expression of CYP drug-metabolizing enzymes. Included is a summary of recent studies that have identified drugs with the potential to regulate drug-metabolizing enzyme activity. Our goal is to inspire the development of clinical drug treatment processes that consider the impact of the inflammatory environment on drug treatment, as well as provide research targets for those studying drug metabolism.

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Section: Introductionmentioning

confidence: 99%

Inflammatory signaling on cytochrome P450-mediated drug metabolism in hepatocytes

Wang

Rao²,

Tan³

et al. 2022

Front. Pharmacol.

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“…Cell culture was performed using high glucose Dulbecco’s Modified Eagle Medium (DMEM; Gibco, Waltham, MA, USA) with 10% ( v / v ) fetal bovine serum (FBS) as previously reported [ 17 ].…”

Section: Methodsmentioning

confidence: 99%

“…To assess the potential role of acetaldehyde in regulating changes in FABP4 , VA-13 ADH+ cells were exposed to EtOH (50 mM). In parallel, HepG2 and HuH7 cells were exposed to an acetaldehyde generating system (AGS) for 48 h [ 17 ]. At experiment completion culture medium was collected and cells processed for RNA/protein analysis.…”

Section: Methodsmentioning

confidence: 99%

“…Using TaqMan probes for FABP4 and AMPKα (Thermo Fisher Scientific, Grand Island, NY, USA) quantitative RT-PCR (qRT-PCR) was performed (TaqMan Universal Master Mix II, Thermo Fisher Scientific). FABP4 and AMPK α mRNA expression was calculated and normalized to 18s-RNA [ 17 ].…”

Section: Methodsmentioning

confidence: 99%

“…Following image capture, densitometric analysis was performed (ImageJ, National Institutes of Health, Bethesda, MD, USA) and protein loading correction was performed to Ponceau S membrane staining or the ratio of phosphorylated to total protein, as appropriate [ 17 ].…”

Section: Methodsmentioning

confidence: 99%

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Role of AMPK-SREBP Signaling in Regulating Fatty Acid Binding-4 (FABP4) Expression following Ethanol Metabolism

Attal

Marrero²,

Thompson³

et al. 2022

Biology

Self Cite

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Fatty acid binding protein-4 (FABP4) is not normally expressed in the liver but is induced in alcohol-dependent liver disease (ALD)). This study sought to identify mechanisms whereby ethanol (EtOH) metabolism alters triglyceride accumulation and FABP4 production. Human hepatoma cells which were stably transfected to express alcohol dehydrogenase (ADH) or cytochrome P4502E1 (CYP2E1) were exposed to EtOH in the absence/presence of inhibitors of ADH (4-methylpyrazole) or CYP2E1 (chlormethiazole). Cells were analyzed for free fatty acid (FFA) content and FABP4 mRNA, then culture medium assayed for FABP4 levels. Cell lysates were analyzed for AMP-activated protein kinase-α (AMPKα), Acetyl-CoA carboxylase (ACC), sterol regulatory element binding protein-1c (SREBP-1c), and Lipin-1β activity and localization in the absence/presence of EtOH and pharmacological inhibitors. CYP2E1-EtOH metabolism led to increased FABP4 mRNA/protein expression and FFA accumulation. Analysis of signaling pathway activity revealed decreased AMPKα activation and increased nuclear-SREBP-1c localization following CYP2E1-EtOH metabolism. The role of AMPKα-SREBP-1c in regulating CYP2E1-EtOH-dependent FFA accumulation and increased FABP4 was confirmed using pharmacological inhibitors and over-expression of AMPKα. Inhibition of ACC or Lipin-1β failed to prevent FFA accumulation or changes in FABP4 mRNA expression or protein secretion. These data suggest that CYP2E1-EtOH metabolism inhibits AMPKα phosphorylation to stimulate FFA accumulation and FABP4 protein secretion via an SREBP-1c dependent mechanism.

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The Synergistic and Opposing Roles of ω-Fatty Acid Hydroxylase (CYP4A11) and ω-1 Fatty Acid Hydroxylase (CYP2E1) in Chronic Liver Disease

James P,

Victor

2024

Genome Biol Mol Genet

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Cytochrome P450 fatty acid hydroxylase consists of members of the CYP4 family that ω-hydroxylate fatty acids and the CYP2E1 that ω-1 hydroxylates fatty acids. Although ω and ω-1 hydroxylation of fatty acids have been thought to play a minor role in fatty acid metabolism (less than 20%), it plays a vital role in excess liver fatty acids overload seen in fasting, diabetes, metabolic disorder, and over-consumption of alcohol and high-fat diet. This pathway provides anabolic metabolites for gluconeogenesis, succinate, and acetate for lipogenesis. The CYP4A and CYP2E1 genes are activated in fasting and several metabolic disorders, suggesting a synergistic role in preventing fatty acid-induced lipotoxicity with the consequence of increased liver cholesterol and lipogenesis leading to increased Lipid Droplet (LD) deposition. During the progression of Metabolic Dysfunction-associated Steatotic Liver Disease (MASLD), activation of Phospholipase A2 (PLA2) releases arachidonic acid that CYP4A11 and CYP2E1 P450s metabolize to produce 20-hydroxyeicosatetraenoic acid (20-HETE) and 19-HETE, respectively. These metabolites have opposing roles in the progression of MASLD and chronic liver disease (CLD). This report discusses the synergistic role of the CYP4A and CYP2E1 P450s in the metabolism of saturated and unsaturated fatty acids and their opposite physiological role in the metabolism of Arachidonic Acid (AA). We finally discuss the role of ethanol in disrupting the synergistic and opposing roles of the CYP4A and CYP2E1 genes in MASLD and CLD.

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Cytochrome P450 2E1‐dependent hepatic ethanol metabolism induces fatty acid‐binding protein 4 and steatosis

Cited by 7 publications

References 52 publications

Inflammatory signaling on cytochrome P450-mediated drug metabolism in hepatocytes

Inflammatory signaling on cytochrome P450-mediated drug metabolism in hepatocytes

Role of AMPK-SREBP Signaling in Regulating Fatty Acid Binding-4 (FABP4) Expression following Ethanol Metabolism

The Synergistic and Opposing Roles of ω-Fatty Acid Hydroxylase (CYP4A11) and ω-1 Fatty Acid Hydroxylase (CYP2E1) in Chronic Liver Disease

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