Mass-Spectrometry-Based Serum Metabolomics of a C57BL/6J Mouse Model of High-Fat-Diet-Induced Non-alcoholic Fatty Liver Disease Development.
Obesity, dyslipidemia, insulin resistance, oxidative stress, and inflammation are key clinical risk factors for the progression of non-alcoholic fatty liver disease (NAFLD). Currently, there is no comprehensive metabolic profile of a well-established animal model that effectively mimics the etiology and pathogenesis of NAFLD in humans. Here, we report the pathophysiological and metabolomic changes associated with NAFLD development in a C57BL/6J mouse model in which NAFLD was induced by feeding a high-fat diet (HFD) for 4, 8, 12, and 16 weeks. Serum metabolomic analysis was conducted using ultrahigh-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS) and gas chromatography-mass spectrometry (GC-MS) to establish a metabolomic profile. Analysis of the metabolomic profile in combination with principal component analysis revealed marked differences in metabolites between the control and HFD group depending upon NAFLD severity. A total of 30 potential biomarkers were strongly associated with the development of NAFLD. Among these, 11 metabolites were mainly related to carbohydrate metabolism, hepatic biotransformation, collagen synthesis, and gut microbial metabolism, which are characteristics of obesity, as well as significantly increased serum glucose, total cholesterol, and hepatic triglyceride levels during the onset of NAFLD (4 weeks). At 8 weeks, 5 additional metabolites that are chiefly involved in perturbation of lipid metabolism and insulin secretion were found to be associated with hyperinsulinemia, hyperlipidemia, and hepatic steatosis in the mid-term of NAFLD progression. At the end of 12 and 16 weeks, 14 additional metabolites were predominantly correlated to abnormal bile acid synthesis, oxidative stress, and inflammation, representing hepatic inflammatory infiltration during NAFLD development. These results provide potential biomarkers for early risk assessment of NAFLD and further insights into NAFLD development.
Yi-Syuan
YS
Lai
Wei-Cheng
WC
Chen
Tien-Chueh
TC
Kuo
Department of Food Science, Rutgers University , New Brunswick, New Jersey 08901, United States.
Chi-Tang
CT
Ho
Ching-Hua
CH
Kuo
Yufeng J
YJ
Tseng
Kuan-Hung
KH
Lu
Shih-Hang
SH
Lin
Suraphan
S
Panyod
Lee-Yan
LY
Sheen
D000818:Animals; D015415:Biomarkers / Q000097:blood; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D059305:Diet, High-Fat / Q000009:adverse effects; D004041:Dietary Fats / Q000009:adverse effects / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D008401:Gas Chromatography-Mass Spectrometry / Q000379:methods; D006801:Humans; D008297:Male; D055432:Metabolomics / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000097:blood* / Q000378:metabolism / Q000473:pathology
D015415:Biomarkers; D004041:Dietary Fats
GC−MS; UHPLC−QTOF−MS; high-fat diet; metabolomics; non-alcoholic fatty liver disease