Plasma oxylipin profile discriminates ethnicities in subjects with non-alcoholic steatohepatitis: An exploratory analysis

Authors: MAZI, TAGREED - University Of California, Davis; BORKOWSKI, KAMIL - University Of California, Davis; FIEHN, OLIVER - University Of California, Davis; BOWLUS, CHRISTOPHER - University Of California, Davis; SARKAR, SOUVIK - University Of California, Davis; MATSUKUMA, KAREN - University Of California, Davis; ALI, MOHAMED - University Of California, Davis; KIEFFER, DOROTHY - University Of California, Davis; WAN, YU-JUI - University Of California, Davis; STANHOPE, KIMBER - University Of California, Davis; HAVEL, PETER - University Of California, Davis; Newman, John; MEDICI, VALENTINA - University Of California, Davis

Submitted to: Metabolites
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/17/2022
Publication Date: 2/19/2022
Citation: Mazi, T.A., Borkowski, K., Fiehn, O., Bowlus, C.L., Sarkar, S., Matsukuma, K., Ali, M.R., Kieffer, D.A., Wan, Y.Y., Stanhope, K.L., Havel, P.J., Newman, J.W., Medici, V. 2022. Plasma oxylipin profile discriminates ethnicities in subjects with non-alcoholic steatohepatitis: An exploratory analysis. Metabolites. 12(2). Article 192. https://doi.org/10.3390/metabo12020192.
DOI: https://doi.org/10.3390/metabo12020192

Interpretive Summary: Non-alcoholic fatty liver disease (NAFLD) includes a range of liver pathologies characterized by slow loss of function and graded increases in inflammation, which can progress to sever complications often associated with cardiovascular disease. While not understood, NAFLD affects Hispanics more often and more seriously than other ethnicities in the U.S. The metabolism of fats produce factors in the body that are involved in regulating inflammatory processes. Changes in these lipid mediators of inflammation are thought to contribute to the initiation and progression of NAFLD. If variations in PUFA metabolism and downstream lipid mediators differ in Hispanic individuals with NAFLD has not been previously evaluated. In this pilot study, fatty acids and an array of their metabolic products were measured in the plasma of White Hispanics (HIS, n=10) and Caucasians (CAU, n=8) with obesity and biopsy -confirmed NAFLD, and compared to a matched group of healthy controls (n =14 HIS; n =8 CAU). The resulting data indicated that HIS individuals had lower levels of omega-3 fatty acids suggesting lower fatty fish consumption, which was independent of either obesity or NAFLD severity. However, HIS subjects with NAFLD had lower levels of specific anti-inflammatory lipid metabolites in their blood that may be linked to the greater disease severity in this ethnic group. Larger studies should be conducted to determine if these changes are robust. If true, they suggest novel therapeutic approaches for the treatment of NAFLD.

Technical Abstract: Non-alcoholic fatty liver disease (NAFLD) includes a range of liver pathologies from steatosis (NAFL) to non-alcoholic steatohepatitis (NASH). With no clear mechanism, it affects Hispanics in the U.S. disproportionately compared to other ethnicities. Polyunsaturated fatty acids (PUFAs) metabolism and downstream inflammatory lipid mediators including oxylipin (OXL) and endocannabinoid (eCB) are altered in NAFLD and thought to contribute to its pathogenesis. It is not clear if variations in PUFA metabolism and downstream lipid mediators characterize ethnicity in NAFLD. This pilot study employed targeted lipidomic profiling for plasma PUFAs, non-esterified OXLs and eCBs in White Hispanics (HIS, n =10) and Caucasians (CAU, n =8) with obesity and biopsy-confirmed NAFL, compared to healthy controls (HC; n =14 HIS; n =8 CAU). Results indicate diminished long chain PUFA profile in HIS with NAFL and NASH, independent of obesity and histological severity. Our data also highlight differences in plasma OXLs profile by ethnicity group in NASH with lower arachidonic acid derived OXLs seen in HIS. We conducted a secondary analysis to compare ethnicities within NASH (n =12 HIS; n =17 CAU). Results show that plasma OXL profile distinguishes ethnicities with NASH and confirmed ethnicity-related differences in arachidonic acid metabolism. It also suggests lower lipoxygenase(s) and higher soluble epoxide hydrolase(s) activities in HIS compared to CAU with NASH. The underlying causes and the implications of these differences on NAFLD severity are not clear and worth investigations. Our findings provide preliminary data suggesting ethnicity-specific plasma signature characterizing NASH that requires further validation.