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Alcoholic liver disease (ALD) results from continuous and heavy alcohol consumption. The current treatment strategy for ALD is based on alcohol withdrawal coupled with antioxidant drug intervention, which is a long process with poor efficacy and low patient compliance. Alcohol-induced CYP2E1 upregulation has been demonstrated as a key regulator of ALD, but CYP2E1 knockdown in humans was impractical, and pharmacological inhibition of CYP2E1 by a clinically relevant approach for treating ALD was not shown. In this study, we developed a RNAi therapeutics delivered by lipid nanoparticle, and treated mice fed on Lieber-DeCarli ethanol liquid diet weekly for up to 12 weeks. This RNAi-based inhibition of Cyp2e1 expression reduced reactive oxygen species and oxidative stress in mouse livers, and contributed to improved ALD symptoms in mice. The liver fat accumulation, hepatocyte inflammation, and fibrosis were reduced in ALD models. Therefore, this study suggested the feasibility of RNAi targeting to CYP2E1 as a potential therapeutic tool to the development of ALD.
ABSTRACT
Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic synovial membrane inflammation. The pathogenesis of RA is unknown, and the related researches mainly focus on inflammation and immune response. Recent researches have found that metabolism is closely related to immunity. Besides, hypoxia and metabolic disorders of glucose and fat can also affect the development, differentiation and function of immune cells, and then lead to occurrence of autoimmune diseases. In recent years, more and more studies have focused on the role of metabolic pathways in the immunity and pathogenesis of RA, in order to explore the pathogenesis of RA from different perspectives and to provide new ideas for the treatment of RA. In this review, we summarized the role of hypoxia, glucose metabolism and fat metabolism in immunity and pathogenesis of RA.
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Objective To investigate the effects of structured triglyceride (STG) and physical mixed medium chain/long chain triglycerides (MCT/LCT) on hepatic and renal function and lipometabolism of patients with acute necrotizing pancreatitis (ANP).Methods The clinical data of 30 patients with ANP who were admitted to the PLA General Hospital between January 2012 and June 2014 were prospectively analyzed.A double-blind,randomized,controlled study was performed in 30 patients who were allocated into the experimental group (15 patients received STG) and the control group (15 patients received physical mixed MCT/LCT).All the patients received isometrical nitrogen and isocaloric parenteral nutrition more than 5 days.The levels of alanine transaminase (ALT),aspartate transaminase (AST),glutamyl-transpeptidase (GGT),alkaline phosphatase (ALP),creatinine (Cr),blood urea nitrogen (BUN),triglyceride (TG) and total cholesterol (TC) were assayed before nutritional support treatment and at day 1,3 and 5 after nutritional support therapy.The measurement data with normal distribution was presented as (x) ± s.The skew distribution data were described as M (range).The comparison between groups were evaluated with an independent sample t test or one-way ANOVA.The count data were analyzed using the chi-square test.Results A total of 30 patients were screened for eligibility.The levels of ALT,AST,GGT,ALP,Cr,BUN,TG and TC were changed within a certain range at day 1,3 and 5 after nutritional support treatment.The levels of ALT,AST,GGT,ALP,Cr,BUN and TC before treatment and at day 5after treatment were changed from 29.0 U/L,25.4 U/L,83.2 U/L,(193 ± 115) U/L,(124 ± 97) μmol/L,(8±6)mmol/L and (2.4±1.1)mmol/L to 29.4 U/L,33.0 U/L,77.7 U/L,(172±74)U/L,(117 ±103)μmol/L,(8 ± 5) mmol/L and (2.3 ± 1.0) mmol/L in the experimental group,and from 23.8 U/L,22.9 U/L,96.2 U/L,(148 ± 108) U/L,(82 ± 57) μmol/L,(9 ± 7) mmol/L and (2.5 ± 0.7) mmol/L to 21.3 U/L,24.5 U/L,127.4 U/L,(179 ± 126) U/L,(80 ± 54) μmol/L,(10 ± 6) mmol/L and (2.4 ±0.8) mmol/L in the control group,respectively.There were no significant differences in the changing trends of the levels of ALT,AST,GGT,ALP,Cr,BUN and TC between the 2 groups (F =0.647,1.186,0.282,0.553,0.862,0.182,0.369,P＞0.05).The level of TG in the experimental group from pre-treatment to day 5 after treatment was changed from (1.5 ± 0.6) mmol/L to (1.5 ± 0.7) mmol/L,with increasing trend from pre-treatment to day 1 after treatment and reaching the normal level at day 3 and 5 after treatment.The level of TG in the control group from pre-treatment to day 5 after treatment was changed from (1.5 ± 0.6) mmol/L to (2.4 ± 0.6) mmol/L,with increasing trend from pre-treatment to day 1,3 and 5 after treatments.There were significant differences in the changing trends of TG before and after nutritional support therapy between the 2 groups (F =7.940,P ＜ 0.05).Conclusion STG and physical mixed MCT/LCT don't influence the hepatic and renal function of patients with ANP undergoing parenteral nutritional support therapy,while STG has a better effect of lipometabolism compared with physical mixed MCT/LCT.Registry This study was registered with the UMIN Clinical Trial Registry with the registry number of UMIN000016958
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Objective To study molecular target of total flavonoid in Ligustrum Lucidum Ait(TFL) on lipometabolism regulation of HepG2 cell.Methods Treatment doses of total flavonoid in Ligustrum Lucidum Ait were determined by MTT and LDH.The expression of lipoprotein lipase(LPL),3-hydroxy-3-methylglutary-coenzyme A redutasein(HMGCR)and peroxisome proliferator-actived receptorsα(PPARα)mRNA of HepG2 cell were determined by reversed transcription polymerase chain reaction(RT-PCR).Results Increased expression of LPL mRNA and PPARαmRNA with TFL(10-6～10-4g/ml)were found in HepG2 cells after treated with TFL(10-5g/ml),but decreased expression of HMGCR mRNA was found after treated with TFL(10-5,10-4 g/ml).Conclusion The potential mechanisms of total flavonoid in Ligustrum Lucidum Ait's hypolipidmic effects may be with its functions of regulating lipoprotein degradation through PPARα-LPL pathway,or regulating steroid biosynthesis by reducing HMGCR.
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@#ObjectiveTo investigate the effect of α-Zearalanol(α-ZAL) on lipometabolism and hemorheology in ovariectomized(OVX) hyperlipidemia rabbits.Methods44 adult virgin female rabbits were divided into 5 groups,group A: normal control;group B: sham+CHO;group C: OVX+CHO;group D: OVX+CHO+17βE_2;group E: OVX+CHO+α-ZAL.Cholesterol(CHO) was fed to rabbits for 12 weeks.Before and after feeding CHO,the serum lipid(TC,TG,LDL-C,HDL-C) were measured;Blood viscosity,plasma viscosity,aggregation index of RBC(AIRC) and fibrinogen were also assayed respectively.ResultsThe serum levels of TC,TG and LDL-C in group B and E were significantly decreased compared with those in group C(P<0.05);the level of blood viscosity,plasma viscosity and AIRC platelet aggregation rate in group D and E were also significantly decreased compared with those in group C(P<0.05).Conclusionα-ZAL can improve vascular function through the adjustment of lipometabolism and hemorheology.