UC Davis

Background/Objective: Nonalcoholic fatty liver disease affects 30% of the world adult population. It comprises a spectrum of liver histopathological presentation that varies from hepatocellular lipid accumulation, or nonalcoholic fatty liver (NAFL), to nonalcoholic steatohepatitis (NASH). Mechanism(s) of NAFLD onset and progression are modulated by a multilayered interaction between genetics, environmental factors, and comorbidities. In the US., the Hispanic population presents with higher rate of NAFLD and more advanced histological scores compared to other ethnicities. However, the underlying metabolic drivers of these observations are not clear. Previous metabolomic studies revealed that NAFLD is associated with several metabolic dysregulations in lipid, carbohydrate, and amino acid metabolism. Also, alterations in polyunsaturated fatty acids (PUFA) and downstream oxidized lipids as oxylipins (OXLs) and endocannabinoids (eCBs) are reported to distinguish different stages of NAFLD. However, if ethnicity-related metabolomic differences exist in NAFLD is not clear. The identification of ethnicity-related metabolomic differences will expand current knowledge with on mechanism(s) of NAFLD onset and progression. It can also identify unshared mechanism(s) that may explain the observed ethnicity-related disparity in NAFLD rate and severity. The objective of this “proof of principle” analyses is to explore metabolomic profiles of a group of Hispanic (HIS) and Caucasian (CAU) subjects with NAFLD and undergoing bariatric surgery Methods: We compared metabolomic profiles in a group of obesity NAFL-HIS and NAFL-CAU subjects to ethnicity-matched lean and healthy control subjects. We also compared the profiles of subjects with NASH to NASH-free (0-NASH) subjects. For this we profiled plasma and liver samples using untargeted, semi-quantitative metabolomic approaches for metabolites related to primary metabolism using gas chromatography/time-of-flight mass spectrometry (GC‐TOF MS); complex lipids using charged surface hybrid liquid chromatography/quadrupole time of flight mass spectrometry (CSH‐QTOF MS/MS); choline and related metabolites using hydrophilic interaction liquid chromatography/quadrupole time of flight mass spectrometer (HILIC-QTOF MS/MS). We also performed a targeted and quantitative lipidomic analysis to profile for plasma fatty acids and related downstream lipid mediators using ultra-high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UPLC-ESI-MS/MS). Results: Findings from current analyses reveal ethnicity-related metabolic perturbation, independent of obesity. Specifically, lean, and healthy HIS subjects showed higher plasma profiles of triglycerides, acylcarnitines, free fatty acids and downstream lipid mediators. Our finding also shows that in NAFL there are ethnicity-related differences in plasma profiles of fatty acids and acylcarnitines. In specific, NAFL-CAU was characterized by higher arachidonic acid, while NAFL-HIS showed lower n-3 PUFA. With the progression to NASH, comparison within ethnicity groups indicated that the hepatic lipidomic profile in NASH-HIS was characterized higher levels of free fatty acids and lipotoxic lipids, suggesting lipotoxicity is involved in the progression of NASH. We also observed a higher hepatic triglyceride with signs of impaired mitochondrial β-oxidation. Remarkably, when comparing between ethnicity groups, the plasma OXLs and eCBs profiles discriminated ethnicities with NASH, independent of histological severity. In specific, NASH-HIS was characterized with lower arachidonic acid derived OXLs, and findings suggest a downregulated lipoxygenase(s) and upregulated soluble epoxide hydrolase(s) activities. Conclusion: The analyses presented in this dissertation highlights the existence of ethnicity-related metabolomic variations in NAFLD that could potentially modulate disease risk and severity in HIS. It also indicates that ethnicity-specific lipidomic signature can distinguish NASH, which needs to be verified in larger studies.