Publications by authors named "A I Cederbaum"

365 Publications

High-fat diet induces fibrosis in mice lacking CYP2A5 and PPARα: a new model for steatohepatitis-associated fibrosis.

Am J Physiol Gastrointest Liver Physiol 2020 11 2;319(5):G626-G635. Epub 2020 Sep 2.

Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia.

Obesity is linked to nonalcoholic steatohepatitis. Peroxisome proliferator-activated receptor-α (PPARα) regulates lipid metabolism. Cytochrome -450 2A5 (CYP2A5) is a potential antioxidant and CYP2A5 induction by ethanol is CYP2E1 dependent. High-fat diet (HFD)-induced obesity and steatosis are more severe in CYP2A5 knockout () mice than in wild-type mice although PPARα is elevated in mice. To examine why the upregulated PPARα failed to prevent the enhanced steatosis in mice, we abrogate the upregulated PPARα in mice by cross-breeding mice with PPARα knockout ) mice to create / mice. The / mice, mice, and mice were fed HFD to induce steatosis. After HFD feeding, more severe steatosis was developed in / mice than in mice and mice. The / mice and mice exhibited comparable and impaired lipid metabolism. Elevated serum alanine transaminase and liver interleukin-1β, liver inflammatory cell infiltration, and foci of hepatocellular ballooning were observed in / mice but not in mice and mice. In / mice, although redox-sensitive transcription factor nuclear factor erythroid 2-related factor 2 and its target antioxidant genes were upregulated as a compensation, thioredoxin was suppressed, and phosphorylation of JNK and formation of nitrotyrosine adduct were increased. Liver glutathione was decreased, and lipid peroxidation was increased. Interestingly, inflammation and fibrosis were all observed within the clusters of lipid droplets, and these lipid droplet clusters were all located inside the area with CYP2E1-positive staining. These results suggest that HFD-induced fibrosis in / mice is associated with steatosis, and CYP2A5 interacts with PPARα to participate in regulating steatohepatitis-associated fibrosis.
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http://dx.doi.org/10.1152/ajpgi.00213.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087345PMC
November 2020

Suppressed hepatocyte proliferation via a ROS-HNE-P21 pathway is associated with nicotine- and cotinine-enhanced alcoholic fatty liver in mice.

Biochem Biophys Res Commun 2019 04 12;512(1):119-124. Epub 2019 Mar 12.

Department of Health Sciences, College of Public Health, East Tennessee State University, Johnson City, TN, 37614, USA. Electronic address:

CYP2A5 is a major enzyme responsible for nicotine and cotinine metabolism in mice. Nicotine and cotinine enhance alcoholic fatty liver in wild type (WT) mice but not in CYP2A5 knockout (KO) mice, and reactive oxygen species (ROS) generated during the CYP2A5-mediated metabolism contributes to the enhancing effect. In combination with ethanol, nicotine and cotinine increased lipid peroxidation end product 4-hydroxynonenal (HNE) in WT mice but not in KO mice. In ethanol-fed KO mice, only 5 and 10 genes were regulated by nicotine and cotinine, respectively. However, in ethanol-fed WT mice, 59 and 104 genes were regulated by nicotine and cotinine, respectively, and 7 genes were up-regulated by both nicotine and cotinine. Plin 2 and Cdkn1a are among the 7 genes. Plin2 encodes adipose differentiation-related protein (ADRP), a lipid droplet-associated protein, which was confirmed to be increased by nicotine and cotinine in WT mice but not in KO mice. Cdkn1a encodes P21 and elevated P21 in nuclei was also confirmed. HNE can increase P21 and P21 inhibit cell proliferation. Consistently, hepatocyte proliferation markers proliferating cell nuclear antigen (PCNA) and Ki67 were decreased in WT mice but not in KO mice by nicotine/ethanol and cotinine/ethanol, respectively. These results suggest that inhibition of liver proliferation via a ROS-HNE-P21 pathway is involved in nicotine- and cotinine-enhanced alcoholic fatty liver.
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http://dx.doi.org/10.1016/j.bbrc.2019.03.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6433518PMC
April 2019

Nicotine enhances alcoholic fatty liver in mice: Role of CYP2A5.

Arch Biochem Biophys 2018 11 15;657:65-73. Epub 2018 Sep 15.

Department of Health Sciences, College of Public Health, East Tennessee State University, Johnson City, TN, 37614, USA; Center of Excellence for Inflammation, Infectious Disease and Immunity, East Tennessee State University, Johnson City, TN, USA. Electronic address:

Tobacco and alcohol are often co-abused. Nicotine can enhance alcoholic fatty liver, and CYP2A6 (CYP2A5 in mice), a major metabolism enzyme for nicotine, can be induced by alcohol. CYP2A5 knockout (cyp2a5) mice and their littermates (cyp2a5) were used to test whether CYP2A5 has an effect on nicotine-enhanced alcoholic fatty liver. The results showed that alcoholic fatty liver was enhanced by nicotine in cyp2a5 mice but not in the cyp2a5 mice. Combination of ethanol and nicotine increased serum triglyceride in cyp2a5 mice but not in the cyp2a5 mice. Cotinine, a major metabolite of nicotine, also enhanced alcoholic fatty liver, which was also observed in cyp2a5 mice but not in the cyp2a5 mice. Nitrotyrosine and malondialdehyde (MDA), markers of oxidative/nitrosative stress, were induced by alcohol and were further increased by nicotine and cotinine in cyp2a5 mice but not in the cyp2a5 mice. Reactive oxygen species (ROS) production during microsomal metabolism of nicotine and cotinine was increased in microsomes from cyp2a5 mice but not in microsomes from cyp2a5 mice. These results suggest that nicotine enhances alcoholic fatty liver in a CYP2A5-dependent manner, which is related to ROS produced during the process of CYP2A5-dependent nicotine metabolism.
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http://dx.doi.org/10.1016/j.abb.2018.09.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6177319PMC
November 2018

Cytochrome P450s and Alcoholic Liver Disease.

Curr Pharm Des 2018 ;24(14):1502-1517

Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, Newyork, United States.

Alcohol consumption causes liver diseases, designated as Alcoholic Liver Disease (ALD). Because alcohol is detoxified by alcohol dehydrogenase (ADH), a major ethanol metabolism system, the development of ALD was initially believed to be due to malnutrition caused by alcohol metabolism in liver. The discovery of the microsomal ethanol oxidizing system (MEOS) changed this dogma. Cytochrome P450 enzymes (CYP) constitute the major components of MEOS. Cytochrome P450 2E1 (CYP2E1) in MEOS is one of the major ROS generators in liver and is considered to be contributive to ALD. Our labs have been studying the relationship between CYP2E1 and ALD for many years. Recently, we found that human CYP2A6 and its mouse analog CYP2A5 are also induced by alcohol. In mice, the alcohol induction of CYP2A5 is CYP2E1-dependent. Unlike CYP2E1, CYP2A5 protects against the development of ALD. The relationship of CYP2E1, CYP2A5, and ALD is a major focus of this review.
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http://dx.doi.org/10.2174/1381612824666180410091511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6053342PMC
October 2019

CYP2A6 is associated with obesity: studies in human samples and a high fat diet mouse model.

Int J Obes (Lond) 2019 03 20;43(3):475-486. Epub 2018 Feb 20.

Department of Health Sciences, College of Public Health, East Tennessee State University, Johnson City, TN, USA.

Background/objectives: CYP2A6 (CYP2A5 in mice) is mainly expressed in the liver. Hepatic CYP2A6 expression is increased in patients with non-alcoholic fatty liver disease (NAFLD). In mice, hepatic CYP2A5 is induced by high fat diet (HFD) feeding. Hepatic CYP2A5 is also increased in monosodium glutamate-induced obese mice. NAFLD is associated with obesity. In this study, we examined whether obesity is related to CYP2A6.

Subjects/methods: Obesity genetic association study: The SAGE is a comprehensive genome-wide association study (GWAS) with case subjects having a lifetime history of alcohol dependence and control subjects never addicted to alcohol. We used 1030 control individuals with self-reported height and weight. A total of 12 single nucleotide polymorphisms (SNP) within the CYP2A6 gene were available. Obesity was determined as a BMI ≥30: 30-34.9 (Class I obesity) and ≥35 (Class II and III obesity). Animal experiment study: CYP2A5 knockout (cyp2a5) mice and wild type (cyp2a5) mice were fed HFD for 14 weeks. Body weight was measured weekly. After an overnight fast, the mice were sacrificed. Liver and blood were collected for biochemical assays.

Results: Single marker analysis showed that three SNPs (rs8192729, rs7256108, and rs7255443) were associated with class I obesity (p < 0.05). The most significant SNP for obesity was rs8192729 (odds ratio (OR) = 1.94, 95% confidence intervals = 1.21-3.10, p = 0.00582). After HFD feeding, body weight was increased in cyp2a5 mice to a greater extent than in cyp2a5 mice, and fatty liver was more pronounced in cyp2a5 mice than in cyp2a5 mice. PPARα deficiency in cyp2a5 mice developed more severe fatty liver, but body weight was not increased significantly.

Conclusion: CYP2A6 is associated with human obesity; CYP2A5 protects against obesity and NAFLD in mice. PPARα contributes to the CYP2A5 protective effects on fatty liver but it opposes to the protective effects on obesity.
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http://dx.doi.org/10.1038/s41366-018-0037-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6102101PMC
March 2019