p16 deficiency promotes nonalcoholic steatohepatitis via regulation of hepatic oxidative stress

Fangqiao Lv; Jun Wu; Dengshun Miao; Wei An; Yutong Wang

doi:10.1016/j.bbrc.2017.03.023

p16 deficiency promotes nonalcoholic steatohepatitis via regulation of hepatic oxidative stress

Biochem Biophys Res Commun. 2017 Apr 29;486(2):264-269. doi: 10.1016/j.bbrc.2017.03.023. Epub 2017 Mar 10.

Authors

Fangqiao Lv¹, Jun Wu², Dengshun Miao², Wei An¹, Yutong Wang³

Affiliations

¹ Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
² The State Key Laboratory of Reproductive Medicine, Department of Anatomy, Histology and Embryology, Nanjing Medical University, Nanjing, China.
³ Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, School of Basic Medical Sciences, Capital Medical University, Beijing, China. Electronic address: [email protected].

PMID: 28286271
DOI: 10.1016/j.bbrc.2017.03.023

Abstract

Nonalcoholic steatohepatitis (NASH) is characterized by excess accumulation of lipids in liver, accompanied with hepatocyte injury, cell death and inflammation. Although p16 is known as tumor suppressor in multiple cancer types, it remains unclear whether p16 plays a critical role in NASH. To determine whether p16 could play a role in the pathogenesis of NASH, wild-type mice and p16^-/- mice were fed on a methionine and choline-deficient (MCD) diet for 3 weeks, and liver steatosis, fibrosis, and inflammation were evaluated. Our data show that p16^-/- mice fed with MCD diet displayed more significant hepatic steatosis, hepatocyte damage, increased oxidative stress and inflammatory cell infiltration compared to MCD-fed WT mice. It was also clear that the increased ROS and the accumulation of lipid in BEL-7402 cells occurred when p16 expression was depleted with siRNA. These findings indicate that p16 may play a critical role in the development of NASH by reining in ROS production and by inhabiting inflammatory response.

Keywords: NASH; Oxidative stress; p16.

MeSH terms

Animals
Cell Line, Tumor
Choline Deficiency / etiology
Choline Deficiency / genetics*
Choline Deficiency / metabolism
Choline Deficiency / pathology
Cyclin-Dependent Kinase Inhibitor p16 / deficiency
Cyclin-Dependent Kinase Inhibitor p16 / genetics*
Cyclin-Dependent Kinase Inhibitor p18 / antagonists & inhibitors
Cyclin-Dependent Kinase Inhibitor p18 / genetics*
Cyclin-Dependent Kinase Inhibitor p18 / metabolism
Disease Models, Animal
Food, Formulated / adverse effects
Gene Expression Regulation
Hepatocytes / metabolism*
Hepatocytes / pathology
Humans
Liver / metabolism
Liver / pathology
Liver Cirrhosis / etiology
Liver Cirrhosis / genetics*
Liver Cirrhosis / metabolism
Liver Cirrhosis / pathology
Male
Methionine / deficiency
Mice
Mice, Inbred BALB C
Mice, Knockout
Non-alcoholic Fatty Liver Disease / etiology
Non-alcoholic Fatty Liver Disease / genetics*
Non-alcoholic Fatty Liver Disease / metabolism
Non-alcoholic Fatty Liver Disease / pathology
Oxidative Stress
RNA, Small Interfering / genetics
RNA, Small Interfering / metabolism

Substances

CDKN2A protein, human
Cdkn2a protein, mouse
Cyclin-Dependent Kinase Inhibitor p16
Cyclin-Dependent Kinase Inhibitor p18
RNA, Small Interfering
Methionine