| As people become more and more stressed,they are at increasing risk of mental illness.Schizophrenia is one of the severe mental illnesses in the world.Antipsychotic medication is the main treatment for schizophrenia.Cumulative evidence has proved that many antipsychotics cause metabolic abnormalities,such as fatty liver and insulin resistance.Fatty liver,a reversible condition in which excessive triglycerides accumulate in hepatocytes,is the symbol of nonalcoholic fatty liver disease(NAFLD).NAFLD will develop into a severe public health problem due to its high prevalence,potential progression to severe liver disorders,and association with cardiovascular disease.Therefore,the study of the pathogenesis of antipsychotic drug-induced fatty liver and strengthening of prevention and treatment strategies not only effectively improve the efficacy of mental illness,but also reduce the morbidity and mortality of patients with fatty liver-related diseases,which is of great significance.The occurrence and development of fatty liver are closely related to the synthesis of lipids in the liver.Two transcription factors SREBP1c and ChREBP in the liver play important roles in the synthesis of intrahepatic fatty acids.In addition,in recent years a large number of clinical and experimental evidences show that adipose tissue,which is the largest endocrine organ and one of the three target organs of insulin,plays a vital role in liver lipid metabolism.Adipose tissue provides up to 70%fatty acids for triglyceride synthesis in the liver.Insulin resistance in adipose tissue reduces lipolysis,increases triglyceride hydrolysis,releases excess fatty acids into the bloodstream,and is taken up by the liver to synthesize triglycerides.Therefore,adipose tissue insulin resistance plays an important role in the pathological changes of liver,including the formation and development of fatty liver.Sulpiride,one of the first generation antipsychotics,becomes a treatment of such a disease for·many developing countries because of its good efficacy,low extrapyramidal side effects and lower cost than atypical antipsychotics(second generation)The first-choice drugs for schizophrenia are also widely used in our country.Although there are some reports of lipid disorders and insulin resistance caused by sulpiride,the pathological mechanism,especially the side effects of the liver,is poorly understood.Therefore,it is necessary to do a further study on side effects of sulpiride.PurposeIn this study,we examined the metabolic effects of chronic treatment with sulpiride,especially focused on fatty liver in rats.Further,we investigated the underlying mechanisms of action to provide a scientific basis for its prevention and treatment.Methods1.The experimental rats were divided into three groups as follows:vehicle control group,sulpiride group and sulpiride + bromocriptine group.Bromocriptine(1 mg/kg)was administered by an oral gavage method at 9:00 am;Sulpiride(80 mg/kg)was injected subcutaneously at 15:00 pm,once daily for 6 weeks.2.At week 5,an oral glucose tolerance test(OGTT)was performed.Plasma concentrations of glucose,insulin,triglyceride and non-esterified fatty acid(NEFA)were determined using enzymatic methods or by ELISA.The indexes of the homeostasis model assessment of insulin resistance(HOMA-IR)and the Adipose tissue insulin resistance(Adipo-IR)were calculated.3.All rats were sacrificed at week 6.The contents of total cholesterol and triglyceride in the liver were determined by enzymatic method,and the degree of hepatic lipid droplet deposition was determined by Oil Red O staining.4.Real-Time PCR was used to determine mRNA expressionin the liver and adipose tissue.5.Western Blot was used to analyze protein expression in the liver and adipose tissue.Results1.Compared with the normal control group,sulpiride group showed increases in fasting plasma prolactin and triglyceride concentrations,and the indexes of HOMA-IR and Adipo-IR(all P<0.05).More importantly,hepatic triglyceride content and Oil Red O stained area were increased(P<0.05).Treatment with bromocriptine attenuated sulpiride-induced hyperprolactinemia(P<0.05),whereas it did not affect the other metabolic parameters in sulpiride-loaded rats(P>0.05).2.Compared with the normal control group,the indexes of HOMA-IR and Adipo-IR,fasting plasma insulin concentration and the plasma fatty acid levels during OGTT in sulpiride model and sulpiride + bromocriptine groups were significantly increased(P<0.05).The differences between sulpiride model and sulpiride +bromocriptine groups were not significant(P>0.05).3.Real-Time PCR analysis revealed that there was no significant difference in hepatic mRNA of carbohydrate-response element-binding protein(ChREBP),sterol regulatory element-binding protein(SREBP)-1c,acetyl-CoA carboxylase(ACC),fatty acid synthase(FAS),stearoyl-CoA desaturase(SCD)1 and adipose tissue insulin receptor substrate(IRS)-2 among normal control,sulpiride model and sulpiride +bromocriptine groups(P>0.05).However,adiposeexpression of IRS-1 mRNA was significantly decreased in sulpiride model and sulpiride + bromocriptine groups(P<0.05),in which there was no significant difference between sulpiride model and sulpiride + bromocriptine groups(P>0.05).4.Western Blot results showed that there was no significant difference in protein expression of hepatic ChREBP and SREBP-lc among normal control,sulpiride model and sulpiride + bromocriptine groups(P>0.05).Adipose IRS-2 total protein and phosphorylated serine731 in IRS-2 were unchanged(P>0.05).However,adipose expression of IRS-1 protein in sulpiride model and sulpiride + bromocriptine groups was decreased(P<0.05).More importantly,fasting phosphorylated proteins of serine307 in IRS-1 and serine473 in Akt were significantly increased(P<0.05).There was no significant difference between sulpiride model and sulpiride + bromocriptine groups(P>0.05).Conclusion1.Chronic application of sulpiride resulted in excessive triglyceride and fatty droplet accumulation in the liver of rats.The results suggest that long-term administration of sulpiride may cause fatty liver.2.Chronic application of sulpiride did not induce change in ChREBP and SREBP-1c,two prominent transcript factors responsible for hepatic fatty acid synthesis in rats.The results suggest that Sulpiride-induced fatty liver is not associated with hepatic fatty acid synthesis.3.Treatment with dopamine D2 receptor agonist bromocriptine did not affect sulpiride-induced fatty liver and expression of the key transcript factors in rats.The results suggest that dopamine D2 receptor is possibly not associated with the occurrence and development of sulpiride-induced fatty liver.4.Chronic application of sulpiride simultaneously increased plasma fatty acid concentrations during OGTT and the index of Adipo-IR,and decreased adipose IRS-1 functional protein expression in rats.The results suggest that long-term administration of sulpiride also causes adipose tissue insulin resistance,which results in over-hydrolysis of adipose triglyceride,over-release fatty acids to the liver,over-synthesis of hepatic triglyceride,and eventually fatty liver. |
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