Ph.D. in Biochemistry and Molecular Biology,2008 Dalian Medical University, Dalian, Liaoning province, China
M.Sc. in Industrial Healthand Occupational Disease,1998 Dalian Medical University, Dalian, Liaoning province, China
B.S. in Medicine (M.D. equivalent) 1991 Shanxi Medical University, Taiyuan, Shanxi province, China
Health Sciences(HSCI )
Alcoholic liver disease (ALD) is a spectrum of disorders from steatosis (fatty liver),
to steatohepatitis (inflammation), fibrosis, cirrhosis, even carcinoma. Cytochrome
P450 2E1 (CYP2E1) can be induced by ethanol consumption. We found that alcoholic steatosis
was developed in wild type (WT) mice but not in CYP2E1 knockout (cyp2e1-/-) mice, when human CYP2E1 was re-introduced to cyp2e1-/- mice, the steatosis induction was restored, suggesting that CYP2E1 is essential for
alcoholic steatosis. Recently, we found that, CYP2A5, another iso-form of cytochrome
P450, can also be induced by chronic ethanol consumption. Very interestingly, the
ethanol induction of CYP2A5 was observed in WT mice but not in cyp2e1-/- mice, suggesting that the ethanol induction of CYP2A5 was CYP2E1-dependent. Ethanol
induction of CYP2A5 was lower in Nrf2 knockout (Nrf2-/-) mice than in WT mice, whereas CYP2E1 induction by ethanol was comparable in WT and
Nrf2-/- mice. These results suggest that ethanol induction of CYP2A5 is regulated by Nrf2
pathway. Furthermore, we observed a more severe ALD in CYP2A5 knockout (cyp2a5-/-) mice than in WT mice, suggesting that CYP2A5 protects against but not promote the
development of ALD. Cadmium chloride (CdCL2) also induces CYP2A5, but cadmium induction of CYP2A5 is independent of CYP2E1 while
it is still regulated by Nrf2. Unlike ethanol, CdCL2-induced liver injury was more severe in WT mice than in cyp2a5-/- mice, suggesting that CYP2A5 contributes to CdCL2-induced liver injury. Comparison of ethanol and cadmium will help dissect the mechanisms
by which CYP2A5 affects liver injury.
Alcohol and tobacco are frequently co-abused. Nicotine is a major addiction-forming
alkaloid in tobacco smoke. In humans, the major nicotine metabolizing enzyme is cytochrome
P450 2A6 (CYP2A6); in mice, it is CYP2A5, a mouse orthologue of human CYP2A6. Recently,
we found that nicotine can enhance alcoholic fatty liver. Very interestingly, the
nicotine enhancing effect was observed in WT mice but not in the cyp2a5-/- mice. Fibroblast growth factor 21 (FGF21), a hepatocytes-derived lipid metabolism
modulator, is elevated in the cyp2a5-/- mice. In the liver, FGF21 is mainly regulated by PPARα. Consistently, PPARα is also
elevated in the cyp2a5-/- mice. Upon ethanol feeding, FGF21 was induced in WT mice, whereas FGF21 was not further
elevated in the cyp2a5-/- mice. FGF21 exerts its action via FGF receptor 1 (FGFR1) and adipose tissue is a
major acting site of FGF21. Liver-specific FGF21 knockout (Fgf21Alb-cre) mice and adipocyte-specific FGFR1 knockout (Fgfr1aP2-cre) mice will be applied to examine the role of FGF21 in alcohol/nicotine liver injury.
FGF21 stimulates adipose tissue to release adipokines, which may in turn act on the
liver. Cell-cell interaction between adipocytes and hepatocytes will be examined
during the development of alcohol/nicotine liver injury.
Generally accepted animal model for ALD is Lieber-DeCarli liquid diet model. However,
Lieber-DeCarli model only induces evident fatty liver and mild inflammation, so-called
early ALD. For liver fibrosis, the common animal models include carbon tetrachloride
(CCL4), thioacetamide (TAA) and bile duct ligation (BDL). CCL4- and TAA-induced liver injuries are dependent on CYP2E1. We found that liver fibrosis
induced by TAA and CCL4 was observed in WT mice but not in cyp2e1-/- mice, confirming the indispensible role of CYP2E1 in TAA and CCL4 hepatotoxicity. TAA is a CYP2A5 inducer but CCL4 is not. While CCL4-induced liver fibrosis was comparable in WT mice and cyp2a5-/- mice, TAA-induced liver fibrosis was more severe in cyp2a5-/- mice than in WT mice, suggesting that TAA-induced liver fibrosis is protected by CYP2A5
(Figure 1). The mechanisms by which CYP2E1 and CYP2A5 influence TAA-induced liver injury/fibrosis
are under investigation.
East Tennessee State University, Assistant Professor, August 2016-present
Icahn School of Medicine at Mount Sinai, New York, NY Research Assistant Professor, January 2009 – August 2016 Postdoctoral fellow,June 2004 - December 2008
Nippon Roche Research Center, Kamakura, Japan Visiting Scientist,February 2001 - July 2001
Dalian Medical University, Dalian, China Lecturer, July 1998 - June 2004 Drug Developing Scientist,July 1996 - June 2004
Nanpiao Coal Mine Hospital, Huludao, China Physician, July 1991 - Aug 1995
Lu Y, Kawashima A, Horii I, Zhong L. Effects of BSO and L-cysteine on drug-induced cytotoxicity
in primary cell cultures: drug-, cell type-, and species-specific difference. Drug
and Chemical Toxicology. 2004; 27(3): 269-280.
Lu Y, Wang X, Cederbaum AI. Lipopolysaccharide-induced liver injury in rats treated with
the CYP2E1 inducer pyrazole. American Journal of Physiology- Gastrointestinal and
Liver Physiology. 2005; 289(2): G308-319.
Lu Y, Kawashima A, Horii I, Zhong L. Cisplatin-induced cytotoxicity in BSO-exposed renal
proximal tubular epithelial cells: sex, age, and species. Renal Failure. 2005; 27(5):629-633.
Wang X, Lu Y, Cederbaum AI. Induction of cytochrome P450 2E1 increases hepatotoxicity caused by
Fas agonistic Jo2 antibody in mice. Hepatology. 2005; 42:400-10.
Lu Y, Cederbaum AI. Cisplatin-Induced Hepatotoxicity Is Enhanced by Elevated Expression
of Cytochrome P450 2E1. Toxicological Sciences. 2006;89(2):515-23.
Lu Y, Cederbaum AI. Enhancement by pyrazole of lipopolysaccharide-induced liver injury:
Role of CYP2E1 and 2A5. Hepatology 2006 Jul;44(1):263-74.
Lu Y, Cederbaum AI. The mode of cisplatin-induced cell death in CYP2E1-overexpressing
HepG2 cells: modulation by ERK, ROS, glutathione, and thioredoxin. Free Radical Biology
and Medicine 2007; 43(7):1061-1075.
Lu Y, Cederbaum AI. CYP2E1and Oxidative Liver Injury by Alcohol. Free Radical Biology
and Medicine 2008; 44(5):723-738.
Lu Y, Zhuge J, Wang X, Bai J, Cederbaum AI. Cytochrome P450 2E1 contributes to ethanol-induced
fatty liver in mice. Hepatology 2008;47(5):1483-1494.
Lu Y*, Gong P* (* equal contribution), Cederbaum AI. Pyrazole induced oxidative liver
injury independent of CYP2E1/2A5 induction due to Nrf2 deficiency. Toxicology 2008
Wang X, Lu Y, Xie B, Cederbaum AI. Chronic ethanol feeding potentiates Fas Jo2-induced hepatotoxicity:
role of CYP2E1 and TNF-alpha and activation of JNK and P38 MAP kinase. Free Radical
Biology and Medicine. 2009 Sep 1;47(5):518-28
Cederbaum AI, Lu Y, Wu D. Role of oxidative stress in alcohol-induced liver injury. Archives of Toxicology.
Lu Y, Cederbaum AI. CYP2E1 potentiation of LPS and TNFalpha-induced hepatotoxicity by
mechanisms involving enhanced oxidative and nitrosative stress, activation of MAP
kinases, and mitochondrial dysfunction. Genes & Nutrition. 2010 June; 5(2): 149–167.
Lu Y, Wu D, Wang X, Ward SC, Cederbaum AI. Chronic alcohol-induced liver injury and oxidant
stress are decreased in cytochrome P4502E1 knockout mice and restored in humanized
cytochrome P4502E1 knock-in mice. Free Radical Biology and Medicine. 2010;49:1406-16.
Lu Y, Bertran S, Samuels TA, Mira-y-Lopez R, Farias EF. Mechanism of inhibition of MMTV-neu
and MMTV-wnt1 induced mammary oncogenesis by RARalpha agonist AM580. Oncogene. 2010
Lu Y, Zhuge J, Wu D, Cederbaum AI. Ethanol induction of CYP2A5: permissive role for CYP2E1.
Drug Metabolism and Disposition. 2011 Feb;39(2):330-6.
Urtasun R, Lopategi A, George J, Leung TM, Lu Y, Wang X, Ge X, Fiel MI, Nieto N. Osteopontin, an oxidant stress sensitive cytokine,
up-regulates collagen-I via integrin α(V) β(3) engagement and PI3K/pAkt/NFκB signaling.
Lu Y, Leung TM, Ward SC, Nieto N. Partial deletion of argininosuccinate synthase protects
from pyrazole plus lipopolysaccharide-induced liver injury by decreasing nitrosative
stress. American Journal of Physiology- Gastrointestinal and Liver Physiology 2012;302(3):G287-95.
Mormone E*, Lu Y* (* equal contribution), Ge X, Fiel MI, Nieto N. Fibromodulin, an Oxidative Stress-Sensitive
Proteoglycan, Regulates the Fibrogenic Response to Liver Injury in Mice. Gastroenterology.
Leung TM*, Lu Y* (* equal contribution), Yan W, Morón-Concepción JA, Ward SC, Ge X, de la Rosa LC,
Nieto N. Argininosuccinate synthase conditions the response to acute and chronic ethanol-induced
liver injury in mice. Hepatology.2012; 55:1596-609.
Lu Y*, Zhang XH* (* equal contribution), and Cederbaum AI. Ethanol induction of CYP2A5:
role of CYP2E1-ROS-Nrf2 pathway. Toxicological Sciences. 2012; 128:427-38.
Bosch A, Bertran SP, Lu Y, Garcia A, Jones AM, Dawson MI, Farias EF. Reversal by RARalpha agonist Am580 of
c-Myc-induced imbalance in RARalpha/RARgamma expression during MMTV-Myc tumorigenesis.
Breast Cancer Research: BCR. 2012; 14(4):R121.
Ge X*, Lu Y* (* equal contribution), Leung TM, Nieto N. Milk osteopontin, a nutritional approach
to prevent alcohol-induced liver injury. American Journal of Physiology- Gastrointestinal
and Liver Physiology. 2013; 304: G929-39.
Lu Y, Ward SC, Cederbaum AI. Nicotine enhances alcohol-induced fat accumulation and collagen
deposit but not inflammation in mouse liver. Alcohol. 2013; 47(5):353-7.
Lu Y, Ward SC, Nieto N. Ethanol plus the Jo2 Fas agonistic antibody-induced liver injury
is attenuated in mice with partial ablation of argininosuccinate synthase. Alcoholism:
Clinical and Experimental Research. 2014 Mar;38(3):649-56.
Ge X, Leung TM, Arriazu E, Lu Y, Urtasun R, Christensen B, Fiel MI, Mochida S, Sørensen ES, Nieto N. Osteopontin
binding to lipopolysaccharide lowers tumor necrosis factor-α and prevents early alcohol-induced
liver injury in mice. Hepatology 2014; 59: 1600-16.
Wang X, Lopategi Aritz, Ge X, Lu Y, Kitamura N, Urtasun R, Tung-Ming Leung, Maria Isabel Fiel and Natalia Nieto. Osteopontin
induces ductular reaction contributing to liver fibrosis. Gut. 2014; 63:1805-1818.
Ge X, Antoine DJ, Lu Y, Arriazu E, Leung TM, Klepper AL, Branch AD, Fiel MI, Nieto N. High Mobility Group
Box-1 (HMGB1) Participates in the Pathogenesis of Alcoholic Liver Disease (ALD). Journal
of Biological Chemistry. 2014; 289: 22672-91.
Cederbaum AI, Lu Y, Wang X, Wu D. Synergistic Toxic Interactions Between CYP2E1, LPS/TNFα, and JNK/p38
MAP Kinase and Their Implications in Alcohol-Induced Liver Injury. Advances in Experimental
Medicine and Biology. 2015; 815:145-72.
Hong F, Liu X, Ward SC, Xiong H, Cederbaum AI, Lu Y. Absence of cytochrome P450 2A5 enhances alcohol-induced liver injury in mice. Digestive
and Liver Disease. 2015; 47(6):470-477.
Leung TM, Lu Y. Alcoholic liver disease: from CYP2E1 to CYP2A5. Current Molecular Pharmacology.
2015, in press. PMID: 26278389
Lu Y, Cederbaum AI. Autophagy Protects Against CYP2E1/Chronic Ethanol-Induced Hepatotoxicity.
Biomolecules. 2015; 5: 2659-2674.
Hong F, Si C, Gao P, Cederbaum AI, Xiong H, Lu Y. The role of CYP2A5 in liver injury and fibrosis: chemical-specific difference. Naunyn-Schmiedeberg's
Archives of Pharmacology. 2016; 389: 33-43.
Arriazu E, Ge X, Leung TM, Magdaleno F, Lopategi A, Lu Y, Kitamura N, Urtasun R, Theise N, Antoine DJ, Nieto N. Signaling via the osteopontin
and high mobility group box-1 axis drives the fibrogenic response to liver injury.
Gut. 2016 Jan 27. pii: gutjnl-2015-310752. doi: 10.1136/gutjnl-2015-310752. [Epub
ahead of print] PMID: 26818617
Lu Y and Cederbaum AI. Alcohol upregulation of cyp2a5: role of reactive oxygen species.
Reactive Oxygen Species, 2016; 1(2):117–130.
CYP2A5 and alcoholic liver disease PI: Yongke Lu Agency: National Institute on Alcohol Abuse and Alcoholism Type: P20AA-017067(PI: Scott Friedman) Pilot Award Dates: 08/01/10-07/31/11
Ethanol induction of CYP2A5 and its toxicological significance PI: Yongke Lu Agency: ABMRF/the Foundation for Alcohol Research Dates: 01/01/12-12/31/13
CYP2A5 and alcoholic liver disease PI: Yongke Lu Agency: National Institute on Alcohol Abuse and Alcoholism Type: R21AA-020877 Dates: 09/01/13-08/31/16
Nicotine and alcoholic liver disease PI: Yongke Lu Agency: National Institute on Alcohol Abuse and Alcoholism Type: R01 AA-024723