The Correlation Between Hyperuricemia And NAFPD Based On Lipidomics

Objective: To investigate the correlation between hyperuricemia and nonalcoholic fatty pancreas disease(NAFPD)based on an animal model of hyperuricemia.Then to find serum biomarkers based on lipidomics and to explore its possible pathogenesis from the perspective of the endoplasmic reticulum stress(ERS)signaling pathway.Methods: 36 SD rats were randomly divided into normal group(CON),high fat group(PO),hyperuricemia group(HUA),hyperuricemia combined with benzbromarone gavage group(HUA+ig),high fat and hyperuricemia group(PH),high fat and hyperuricemia combined with benzbromarone gavage group(PH+ig).Modeling was performed in two stages.The first stage(1-8 weeks)was fed with different feeds,and the second stage(9-12 weeks)used 2% benzbromarone suspension for intragastric administration to block uric acid metabolism.serum uric acid(SUA),serum creatinine(SCr)and triacylglycerol(TAG)were detected.The pathological changes of the pancreas were observed by light microscopy after HE staining.The serum samples were detected by lipidomics technology.Multivariate statistical analysis was used to compare the differences of lipid metabolism profiles between the groups.Then the differential lipid metabolites were screened and combined with Met PA online database to analyze the relevant metabolic pathways.The main m RNA and proteins of ERS signaling pathways were evaluated by RTPCR and Western blot.Results:1.SUA level: The SUA level in HUA group,HUA+ig group,PH group,and PH+ig group gradually increased since the 2nd week,and the four groups were significantly higher than CON group since the 4th week(P<0.05).The SUA level in PH group and PH+ig group was significantly higher than the other four groups(P<0.05).At the 12 th week,compared the HUA+ig group with HUA group and the PH+ig group with PH group,the SUA level all decreased(P<0.05).2.SCr level: The SCr level in the PO group was not significantly different from that in the CON group(P>0.05).Compared with the CON and PO groups,the SCr level in HUA group and HUA+ig group was slightly increased(P>0.05).The SCr level in PH group and PH+ig group was significantly higher than the other four groups since the 2nd week(P<0.05).At the 12 th week,the SCr level in PH+ig group decreased than that in PH group(P<0.05),but was still significantly higher than the other four groups(P<0.05).3.TAG level: The TAG level in the PO group gradually increased,and it was significantly higher than the other five groups since the 4th week(P<0.05).Compared with the CON group,the HUA group and HUA+ig group had no significant difference at the early stage of the experiment(P>0.05),and was higher than CON group since the 8th week(P<0.05).At the 12 th week,the TAG level in HUA+ig group decreased than that in HUA group(P<0.05).Compared with the CON group,the PH group and PH+ig group had no significant difference at the early stage of the experiment(P>0.05),and was higher than CON group since the 8th week(P<0.05).At the 12 th week,the TAG level of the two groups decreased,which was not statistically significant compared with the CON group(P>0.05).4.Pathological changes: In PO group,most of the SD rats pancreatic islet and acinar cells showed a small to medium fatty change.In HUA group,only a part of SD rats islet cells and pancreatic acinar cells showed a small amount of fine fatty change.In PH group,most of the SD rats pancreatic islet and acinar cells showed moderate fatty change in medium volume,and some fused into larger fatty change.According to the severity of NAFPD from mild to severe,the order was CON group,HUA group,PO group,and PH group.5.Lipidomics analysis results: The potential serum biomarkers were as follows:21 in the CON and HUA groups,34 in the CON and PO groups,38 in the CON and PH groups,30 in the HUA and PO groups,29 in the PH and HUA groups,and 32 in PH group and PO group.These metabolites mainly included sphingolipids(SM),cholesterolesters(CE),fatty acids(FFA),triacylglycerols(TAG)and phosphatidylcholines(PC)and lysophosphatidylcholine(LPC),phosphatidylethanolamine(PE),lysophosphatidylethanolamine(LPE).6.RT-PCR evaluation results: Compared with the CON group,the expressions of SREBP-1c and FAS m RNA in the PO group,HUA group,and PH group were all increased(P<0.05).Compared the HUA+ig group with HUA group and the PH+ig group with PH group,the expressions all decreased(P<0.05).7.Western blot evaluation results: Compared with the CON group,the expressions of GRP78 protein in the PO group,HUA group,and PH group were all increased(P<0.05).Compared the HUA+ig group with HUA group and the PH+ig group with PH group,the expressions all decreased(P<0.05).Conclusions:1.Persistent hyperuricemia may be one of the causes of NAFPD.Hyperlipidemia with hyperuricemia may aggravate the pathophysiology of NAFPD.2.Compared with hyperuricemia,hyperlipidemia mainly affects TAG metabolism.Hyperlipidemia combine with hyperuricemia will exacerbate the glycerophospholipid metabolism disorder,which may be related to cell membrane damage and remodeling.3.TAG,PC,LPC,PE,and LPE may be the potential serum biomarkers of NAFPD.SM may be a special biomarker of NAFPD affected by hyperuricemia.4.The reason that hyperuricemia affects pancreatic lipid metabolism disorder may be due to increased de novo lipid synthesis through ERS signaling pathway.