Liver-specific NG37 overexpression leads to diet-dependent fatty liver disease accompanied by cardiac dysfunction

Xin Zhou, Meng Meng Xu, Liyang Wang, Yulian Mu, Rui Feng, Zhilong Dong, Yuexin Pan, Xunzhang Chen, Yongfeng Liu, Shangen Zheng, Donald D. Anthony, Jianjie Ma, William B Isaacs, Xuehong Xu

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalGenes and Nutrition
Volume11
Issue number1
DOIs
StatePublished - 2016

Fingerprint

High Fat Diet
Fatty Liver
Liver Diseases
Diet
Transgenic Mice
Liver
Cardiac Arrhythmias
Hepatocytes
Genetic Terminator Regions
Body Weight
Weights and Measures
Polyadenylation
Hepatomegaly
3' Untranslated Regions
Genetic Predisposition to Disease
Bradycardia
Lipid Metabolism
X-Ray Diffraction
Genes
Albumins

Keywords

  • Cardiac dysfunction
  • Diet-dependent
  • Liver enlargement
  • NG37

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Genetics

Cite this

Liver-specific NG37 overexpression leads to diet-dependent fatty liver disease accompanied by cardiac dysfunction. / Zhou, Xin; Xu, Meng Meng; Wang, Liyang; Mu, Yulian; Feng, Rui; Dong, Zhilong; Pan, Yuexin; Chen, Xunzhang; Liu, Yongfeng; Zheng, Shangen; Anthony, Donald D.; Ma, Jianjie; Isaacs, William B; Xu, Xuehong.

In: Genes and Nutrition, Vol. 11, No. 1, 2016.

Research output: Contribution to journalArticle

Zhou, X, Xu, MM, Wang, L, Mu, Y, Feng, R, Dong, Z, Pan, Y, Chen, X, Liu, Y, Zheng, S, Anthony, DD, Ma, J, Isaacs, WB & Xu, X 2016, 'Liver-specific NG37 overexpression leads to diet-dependent fatty liver disease accompanied by cardiac dysfunction', Genes and Nutrition, vol. 11, no. 1. https://doi.org/10.1186/s12263-016-0529-z
Zhou, Xin ; Xu, Meng Meng ; Wang, Liyang ; Mu, Yulian ; Feng, Rui ; Dong, Zhilong ; Pan, Yuexin ; Chen, Xunzhang ; Liu, Yongfeng ; Zheng, Shangen ; Anthony, Donald D. ; Ma, Jianjie ; Isaacs, William B ; Xu, Xuehong. / Liver-specific NG37 overexpression leads to diet-dependent fatty liver disease accompanied by cardiac dysfunction. In: Genes and Nutrition. 2016 ; Vol. 11, No. 1.
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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.",
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AU - Zhou, Xin

AU - Xu, Meng Meng

AU - Wang, Liyang

AU - Mu, Yulian

AU - Feng, Rui

AU - Dong, Zhilong

AU - Pan, Yuexin

AU - Chen, Xunzhang

AU - Liu, Yongfeng

AU - Zheng, Shangen

AU - Anthony, Donald D.

AU - Ma, Jianjie

AU - Isaacs, William B

AU - Xu, Xuehong

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

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KW - Diet-dependent

KW - Liver enlargement

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