Therapeutic Effect Of Quercetin On The Dysfunction Of Lipid Metabolism And Neuropsychiatric Behaviors In A NAFLD Rat Model And Its Potential Mechanism

Nonalcoholic fatty liver disease(NAFLD)is a chronic liver injury defined as excessive intrahepatic fat accumulation in the absence of increased alcohol consumption or other causes of liver steatosis.In addition to lipid metabolism disorders and liver function impairment,it has been reported that NAFLD could induce a variety of extrahepatic injuries including neuropsychiatric dysfuntion.Meanwhile,increasing evidence show that triggering receptor expressed on myeloid cells1/2(TREM1/2)is involved in the pathogenesis of NAFLD process,and become a potential target for the treatment of NAFLD.Quercetin(quercetin,QUE)is a kind of natural polyhydroxy flavonoid compound with many proven health benefits including anti-inflammatory,anti-aging,anti-cancer activity,anti-metabolic syndrome,and neuroprotective effects.In this study,a rat model of NAFLD was induced by a high-fat diet,the changes of bodyweight,lipid metabolism,liver morphology and function were measured.Moreover,a series of behavior tests were used to assess the sensory,motor,emotion,and learning and memory abilities of the rats.Furthermore,the therapeutic effect of QUE on the dysfunction of lipid metabolism and neuropsychiatric behaviors in NAFLD rats was investigated,and the potential mechanisms were explored.Objective: To explore the therapeutic effect of QUE on the dysfunction of lipid metabolism,liver morphology and function,and neuropsychiatric behavior in a high-fat diet-induced rat NAFLD model by a,and the changes of and explore the potential mechanisms.Methods:1.Establishment of NAFLD rat model via a high-fat dietMale Sprague Dawley(SD)rats were randomly divided into control group and model group,and the NAFLD rat model was established by a 4 consecutive weeks’ high-fat diet.The plasma level of glucose,total cholesterol(TC),triglyceride(TG),alanine aminotransferase(ALT),high-density lipoprotein cholesterol(HDL-C),and low-density lipoprotein cholesterol(LDL-C)were test by chemiluminescence method.Plasma concentration of nesfatin-1,leptin,free fatty acid(FFA)and insulin were determined by enzyme linked immunosorbent assay(ELISA).Liver weight and liver index were investigated,and the morphological changes of the liver tissue were observed by HE staining and oil red O staining.The neuropsychiatric behaviors were evaluated through the open field test(OFT),the sucrose preference test(SPT),Morris water maze(MWM),and the forced swimming test(FST).and the morphological changes of the hippocampus were observed by HE staining and silver staining.The protein expression of copine6 in the hippocampus and the prefrontal cortex(PFC)were examined via Western blotting method.2.Effect of QUE on Lipid Metabolism Disorder and Neuropsychiatric injury in NAFLD Rats and the potential mechanisms.Male SD rats were randomly divided into 8 groups including the control gr oup,NAFLD model group,control + QUE group(40 mg/kg),QUE group(80,40,20 mg/kg),Sitagliptin group(10 mg/kg)and Donepezil group(1 mg/kg).Rats in the control group and the control + QUE group(40 mg/kg)were given a s tandard control feed and rats in the other group were given a 60% high-fat diet.The drugs were given after 4 consecutive fed with different diets according to the doses mentioned above.After 4 weeks’ course of treatment,the neuropsych iatric behaviors were evaluated,and the plasma level of glucose,TC,and TG were tested.Meanwhile,the plasma contents of corticosterone(CORT),vitamin D(VD),TREM1,and TREM2 were measured.The morphological changes of the liver and hippocampus were detected.Furthermore,the m RNA expression of C RH in the hyperthalamus was measured.The protein expression of TREM1,TR EM2,Synapsin-1(Syn-1)and Synaptatogmin-1(Syt-1)in the hippocampus and the PFC were also examined.Results:1.Compared with the control group,rats in the model group showed an increase of bodyweight.liver weight,liver index,and plasma ALT and glucolipid contents.The plasma concentration of nesfatin-1 in the NAFLD model group was increased while the plasma leptin level was decreased.Results of HE and O staining showed inflammation and hepatocyte ballooning in the liver of model rats.Behavioral results indicated a decline of learning and memory ability,accompanied with depressive behaviors in NAFLD model rats.Results of hippocampal HE and silver staining showed an impairment of hippocampal neurons.The results of Western blotting showed that the protein expression of copine6 in the hippocampus and PFC were decreased,2.Compared with model group,QUE(80,40,20 mg/kg)ig had no significant effect on the changes of body weight and blood glucose in NAFLD model rats,but QUE(80,40,20 mg/kg)ig could decrease the plasma levels of TG and TC.The results of HE and oil red O staining of liver confirmed that QUE could reduce the inflammation and hepatocyte ballooning in the liver of NAFLD rats.Behavioral results showed QUE(80,40,20 mg/kg)ig could decrease escaping latency,increase duration in the platform quadrant in the MWM test,increase sucrose preference index in the SPT and decrease the immobility time in the FST of NAFLD rats.The results of HE and silver staining also proved that QUE could improve the neuronal damage in the hippocampus of NAFLD rats.The plasma CORT concentration and the CRH m RNA expression in hypothalamus were increased in NAFLD model rats,which could be reversed in the QUE groups.Results of Western blotting indicated that protein expression of Syn-1,Syt-1 and TREM1 were increased and protein expression of TREM2 was decreased in QUE group as compared with those in the NAFLD model group.Conclusion:1.A NAFLD rat model was successfully induced by a high-fat diet,as indicated by obesity,hyperglycemia,hyperlipidemia,and liver morphology and functional impairment,accompanied with the abnormal neuropsychiatric behaviors including anhedonia,despair behaviors and dysfunction of learning and memory ability,the mechanism of which might be associated with the increase plasma nesfatin-1concentration and the decreased hippocampal copine6 expression.2.QUE could improve the lipid metabolism disorder,liver function damage and neuropsychiatric behavior abnormalities in NAFLD rats,the mechanism of which might be related to its ability in balancing the lipid metabolism and regulation of HPA axis activity,synaptic plasticity,and the expression of TREM1 and TREM2 in the hippocampus and PFC.