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

Abstract

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.

• Authors: Xue Chen, Kesheng Wang, Arthur I Cederbaum, Yongke Lu
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 512 Issue 1 Pg. 119-124 (04 23 2019) ISSN: 1090-2104 [Electronic] United States
• PMID: 30876690 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• Aldehydes
• Cdkn1a protein, mouse
• Cyclin-Dependent Kinase Inhibitor p21
• Perilipin-2
• Plin2 protein, mouse
• Reactive Oxygen Species
• Nicotine
• Aryl Hydrocarbon Hydroxylases
• Cyp2a5 protein, mouse
• Cytochrome P450 Family 2
• 4-hydroxy-2-nonenal
• Cotinine

Topics

• Aldehydes (metabolism)
• Animals
• Aryl Hydrocarbon Hydroxylases (deficiency, genetics)
• Cell Proliferation (drug effects)
• Cotinine (administration & dosage)
• Cyclin-Dependent Kinase Inhibitor p21 (genetics, metabolism)
• Cytochrome P450 Family 2 (deficiency, genetics)
• Disease Models, Animal
• Fatty Liver, Alcoholic (genetics, metabolism, pathology)
• Female
• Hepatocytes (metabolism, pathology)
• Liver Regeneration (drug effects, genetics)
• Mice
• Mice, Knockout
• Nicotine (administration & dosage)
• Perilipin-2 (genetics, metabolism)
• Reactive Oxygen Species (metabolism)
• Signal Transduction
• Up-Regulation (drug effects)