Abstract

Title	Mice Deficient in HLJ1 Exhibit Impaired ER Stress Mediated Fatty Liver and Defects in Liver Responses to Environmental Toxics
Speaker:	Min Hui Chien
Author:	M.H. Chien^1,2*, T.C. Lin³, K.Y. Su^2,3, P.C. Yang^1,2, H.Y. Chen³, K.C. Li³, S.L. Yu^2,4
Affiliation:	¹Department of Internal Medicine, National Taiwan University Hospital, ²Center for Genomic Medicine, College of Medicine, National Taiwan University, ³Institute of Statistical Science, Academia Sinica, ⁴Institute of Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan R.O.C.. *julia861009@hotmail.com
Background and aim: HLJ1 (known as DNAJB4), a member of the heat shock protein (HSP) chaperone family, is a novel tumor suppressor gene in non-small cell lung cancer. However, the underlying mechanism of HLJ1 remains largely unknown in tumorigenesis. Although HLJ1 has been characterized in tumor cells, it was ubiquitously expressed in many normal organs especially highly in the liver. HSPs are involved in the essential normal physiological functions including protein folding, immunologic processes, cell cycle regulation and basal metabolism, and their activity can be induced by environmental stresses, toxins or pathogen infection. Therefore, we disrupt the HLJ1 gene in mice by homologous recombination based gene targeting strategy to further understand the biological roles of HLJ1 in vivo. Result: Mice deficient in HLJ1 (HLJ1^-/- mice) were viable and fertile with no macroscopic abnormality except lipid metabolism. The expression of fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC), enzymes of triglyceride synthesis, was elevated in HLJ1^-/- mice. We also found that HLJ1^-/- mice had higher ER stress in PKER-like ER kinase (PERK) and JNK pathways. The impaired ER stress leaded to sensitize environmental stress challenges such as high fat diet and acetaminophen induced liver failure. Furthermore, expression microarray analysis found that HLJ1 was involved in cellular processes related to lipid metabolism, small molecule metabolism and response to stimulus. Whether the abnormalities we observed were due to HLJ1 dependent unfolding protein system is under investigation. Conclusion: Taken together, the establishment of this animal model is not only helpful for imitating Nonalcoholic fatty liver disease (NAFLD) but also provides a therapeutic or a preventing strategy for eliminating toxicity in the liver through enhancing HLJ1 expression.