title: Liver-specific NG37 overexpression leads to diet-dependent fatty liver disease accompanied by cardiac dysfunction.
abstract: BACKGROUND
  Environmental factors are well-known causes of diseases. However, aside from a handful of risk indicators, genes' encoding susceptibility to chronic illnesses and their associated environmental triggers are largely unknown. In this era of increasingly rich diets, such genetic predispositions would be immensely helpful from a public health perspective. The novel transgenic mouse model with liver-specific NG37 overexpression characterized in this article identifies the diet-dependent function of NG37 in the pathogenesis of fatty liver disease and cardiac arrhythmia.
  
  
  RESULTS
  The liver-specific NG37 overexpression transgenic mouse model described here was generated using the Alb-SV40 polyA expression plasmid backbone. NG37 cDNA under control of the albumin promoter for liver-specific expression was fused with a 5' terminal M2 FLAG sequence and a SV40 early region transcription terminator/polyadenylation site attached at the 3'-UTR. These NG37 transgenic mice developed normally and were physiologically normal on a standard diet. However, in comparison to non-transgenic (nTG) litter mates, these mice develop dramatic phenotypes within 12-18 days of starting a high-fat diet: (i) increased body weight (28.5 ± 12.3 g), (ii) increased liver weight (87.4 ± 35.7 mg), (iii) increased heart weight (140 ± 38.4 mg), and (iv) cardiac arrhythmia. The enlarged livers of high-fat diet NG37 transgenic mice was histologically similar to human fatty liver disease and contained Maltese cross birefringent active depositions in hepatocytes that are indicative of fatty liver disease. We also confirmed via X-ray diffraction the steatotic vesicles in the diseased hepatocytes of our high-fat diet NG37 mice was composed of cholesteryl derivatives also found in human fatty liver disease. In addition to cardiac enlargement, NG37 transgenic mice on high-fat diet also exhibited highly irregular bradycardia not present in either high-fat diet nTG littermates or normal-diet transgenic litter mates.
  
  
  CONCLUSIONS
  The dramatic high-fat diet-dependent symptoms (increased body weight, cardiac enlargement, fatty liver, and cardiac arrhythmias) characterized in our liver-specific NG37 overexpression mouse model identifies NG37 as a gene encoding latent lipid metabolism pathology induced only in the presence of an environmental factor relevant to human health: high-fat diet.
authors.affiliation: College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi 710062 China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Pharmacology, Duke University Medical Center, Durham, NC 27708 USA.
authors.forename: MengMeng
authors.initials: M
authors.lastname: Xu
authors.affiliation: College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi 710062 China.
authors.forename: Liyang
authors.initials: L
authors.lastname: Wang
authors.affiliation: State Key Laboratory for Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, 100193 China.
authors.forename: Yulian
authors.initials: Y
authors.lastname: Mu
authors.affiliation: College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi 710062 China.
authors.forename: Rui
authors.initials: R
authors.lastname: Feng
authors.affiliation: Lanzhou University School of Medicine, Lanzhou, 730030 China.
authors.forename: Zhilong
authors.initials: Z
authors.lastname: Dong
authors.affiliation: Case Western Reserve University School of Medicine, Cleveland, OH 44106 USA.
authors.forename: Yuexin
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Wuhan General Hospital of Guangzhou Military Command, Wuhan, Hubei 430070 China.
authors.forename: Xunzhang
authors.initials: X
authors.lastname: Chen
authors.affiliation: State Key Laboratory for Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, 100193 China.|College of Food Engineering and Nutritional Science, Shaanxi Normal University, Xi'an, Shaanxi 710062 China.
authors.forename: Yongfeng
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Wuhan General Hospital of Guangzhou Military Command, Wuhan, Hubei 430070 China.
authors.forename: Shangen
authors.initials: S
authors.lastname: Zheng
authors.affiliation: Case Western Reserve University School of Medicine, Cleveland, OH 44106 USA.
authors.forename: Donald D
authors.initials: DD
authors.lastname: Anthony
authors.affiliation: Ohio State University School of Medicine, Columbus, OH 43210 USA.
authors.forename: Jianjie
authors.initials: J
authors.lastname: Ma
authors.affiliation: Johns Hopkins School of Medicine, Baltimore, MD 21287 USA.
authors.forename: Williams B
authors.initials: WB
authors.lastname: Isaacs
authors.affiliation: College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi 710062 China.
authors.forename: Xuehong
authors.initials: X
authors.lastname: Xu
keywords: Cardiac dysfunction; Diet-dependent; Liver enlargement; NG37