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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.

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