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OBJECTIVE To explore the mechanism of Yishen tongluo formula （YSTLF） in improving abnormal lipid metabolism based on the sterol regulatory element binding proteins （SREBPs） pathway. METHODS Using C57BLKS/J （db/db） mice as model and C57BLKS/J （db/m） mice as normal control， the mechanism of 1， 2.5 and 5 g/kg YSTLF improving abnormal lipid metabolism of db/db mice was investigated by determining the liver coefficient， the contents of serum total cholesterol （TC）， triglyceride （TG）， low-density lipoprotein （LDL） and high-density lipoprotein （HDL）， observing steatosis and lipid accumulation in liver tissue of mice， detecting the protein expressions of SREBP-1 and SREBP-2 as well as mRNA transcription levels of Srebp- 1c， Srebp-2 and their downstream lipid metabolism-related target genes （Fasn， Acc1， Scd5， Fads1， Hmgcr， Dhcr24， Insig-1， Fdps） in liver tissue of mice. Using low-fat cultured human liver cancer cell HepG2 as an in vitro cell model for abnormal lipid metabolism， and 25-HC （SREBPs inhibitor， 10 μmol/L） as the control， the effects of 125， 250 and 500 μg/mL YSTLF on protein expressions of SREBP-1 and SREBP-2 as well as mRNA transcription of SREBP-1c， SREBP-2 and their downstream lipid metabolism-related target genes were investigated to verify the mechanism in vitro. RESULTS 1， 2.5， 5 g/kg YSTLF significantly reduced the levels of TC， TG and LDL， the percentage of lipid droplet-positive region in liver tissue and liver coefficient， significantly down-regulated protein expressions of Pre-SREBP-1， n-SREBP-1， Pre-SREBP-2 and n-SREBP-2， and mRNA transcription of Srebp-1c， Srebp-2 and their downstream target genes in liver tissue， while significantly increased HDL level， with statistical significance （P＜0.05 or P＜0.01）. In the cell experiment in vitro， the expressions of the above-mentioned proteins and genes in the cells treated with YSTLF at 125， 250 and 500 μg/mL for 24 hours were consistent with those in the animal experiment； there was no significant difference in the expressions of the above-mentioned proteins and genes between inhibitor control group and 250， 500 μg/mL YSTLF groups （P＞0.05）. CONCLUSIONS YSTLF can regulate the expression of transcription factor SREBPs， so as to inhibit the high expression of fatty acid and cholesterol synthesis-related genes， promote the degradation of TC and TG， improve the abnormality of lipid metabolism and inhibit lipid accumulation， thus playing the role of lipid-lowering.
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Objective To explore the effect of aerobic exercise on blood lipid of hyperlipidemia rats and its mechanism. Methods A total of 120 healthy male SD rats aged 8 weeks were randomized into normal control group, high-fat diet (HF) group, SBC-115076 group and aerobic exercise group, with 30 rats in each group. The rats in the normal control group were fed with standard diet, and the rats in the other 3 groups were fed with HF to establish hyperlipidemia rat model. The rats in the SBC-115076 group were injected with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor SBC-115076 (8 mg/kg) once a week for 8 weeks, and the rats in the aerobic exercise group underwent swimming without load 6 days a week for 8 weeks. After 8 weeks, the rats were sacrificed and the blood samples were collected to determine the levels of serum triglyceride (TG), total cholesterol (TC), low-density lipoprotein (LDL) and high-density lipoprotein (HDL). Pathological changes of thoracic aorta were observed using H-E staining. The mRNA and protein expression levels of PCSK9, low-density lipoprotein receptor (LDLR) and sterol regulatory element binding protein (SREBP) in the hepatic tissues were detected by quantitative real-time PCR, Western blotting and immunofluorescence. Results Compared with the normal control group, the levels of serum TG, TC and LDL of the rats were significantly higher in the HF group, and the level of HDL was significantly lower (P<0.01). Compared with the HF group, the levels of serum TG, TC and LDL of the rats were significantly lower in the SBC-115076 and aerobic exercise groups, and the level of HDL was significantly higher (P<0.01). In the HF rats, the aortic tunica intima was thickened and endothelial cells were damaged and exfoliated. Compared with the HF group, the aortic intima thickening was reduced and endothelial damage was less in the aerobic exercise group. Compared with the normal control group, the mRNA and protein expression levels of PCSK9, SREBP1 and SREBP2 were significantly higher in the HF group, and the mRNA and protein expression levels of LDLR were significantly lower (P<0.01). Compared with the HF group, the mRNA and protein expression levels of PCSK9, SREBP1 and SREBP2 were significantly lower, and the mRNA and protein expression levels of LDLR were significantly higher (P<0.01). Conclusion Aerobic exercise can down-regulate the expression of TG, TC and LDL, up-regulate the expression of HDL, and alleviate the intimal thickening of aorta. The mechanism may be related to down-regulating the expression of PCSK9 and SREBPs, thus eliminating the inhibition of LDLR.
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Sterol regulatory element binding proteins (SREBPs) are the major transcription factors regulating cholesterol, fatty acid and triglyceride biosynthesis and control the expression of key genes such as lipogenesis and uptake. In this review, we summarize the processing of SREBPs and their interactions with insulin, cyclic adenosine monophosphate (cAMP), and liver X receptor (LXR) for the synthesis and metabolism of lipid, and combine the latest researches to illustrate the function of SREBPs. These findings suggest that inhibition of SREBPs can be a new strategy for the treatment of metabolic diseases, such as type Ⅱ diabetes, insulin resistance, fatty liver, atherosclerosis and tumors.
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Sterol regulatory element-binding proteins(SREBPs),as a major regulator of liposome in vivo,plays an important role in controlling liver lipid synthesis and inducing expression of genes involved in fatty acid,triglyceride and cholesterol synthesis.Part of the traditional Chinese medicine and its derivatives through the SREBP can be tar-get treatment of lipid metabolism related diseases.
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Alcoholic fatty liver disease (AFLD) is the first step to wards alcoholic liver disease (ALD). A beffer knowledge of AFLD will contribute to the prevention and therapy of ALD. It has been found that the occurrence and development of AFLD mainly involve the pathways of cytochrome P450 (CYP2E1),peroxisome proliferator-activated receptor α(PPARα),sterol regulatory element-binding proteins (SREBPs),AMP-activated protein kinase(AMPK),sirtuin 1(SIRT1),adiponectin and insulin.This review focuses on the importance of PPARα,SREBPs and AMPK pathway in alcoholic steatosis.It's reported that alcohol and its metabolite acetaldehyde inhibit PPARα and AMPK,and activate SREBP protein directly or indirectly,leading to liver lipid metabolic disorders,reducing the ability of fatty acid oxidation,causing lipid accumulation, and eventually inducing AFLD. Additionally, this review outlines the prospect of a therapeutics of AFLD targetting PPARα,SREBPs and AMPK.
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ObjectiveTo investigate the effects of niacin on the lipid metabolism in rat model of non-alcoholic fatty liver disease (NAFLD). MethodsForty Sprague-Dawley rats were randomly divided into control group, model group, intervention group 1 (0.5% niacin), and intervention group 2 (1% niacin). Rats were fed with high-fat diet for 8 weeks to induce an NAFLD model. The serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase, levels of total cholesterol (TC), triglyceride, and free fatty acid in serum and liver tissue, and level of malondialdehyde (MDA) in liver tissue were measured using assay kits. The morphological and histopathological changes in the liver were observed under a microscope. Comparison of data between groups was made by univariate analysis of variance using SPSS software; moreover, least significant difference test (equal variance assumed) and Tamhane's T2 test (equal variance not assumed) were used for pairwise comparison. ResultsCompared with the model group, every intervention group had significantly lower levels of ALT, TC, AST, TG, and FFA (all P＜0.05) in serum and level of MDA in liver tissue (P＜0.05), and had significantly increased expression of PPARα mRNA (P＜0.05), DGAT2 mRNA (P＜0.05), and SREBP1c mRNA (P＜0.05). Intervention group 2 had significantly reduced expression of DGAT2 mRNA and SREBP1c mRNA compared with intervention group 1 (P＜0.05). Compared with the model group, the intervention groups had relieved fatty degeneration of hepatocytes and alleviated inflammatory cell infiltration in the centrilobular portion of the liver. ConclusionNiacin regulates lipid metabolism in NAFLD animal models, reduces lipid oxidative stress, and significantly reduces liver steatosis and fibrosis by regulating the expression of PPARα mRNA, DGAT2 mRNA, and SREBP1c mRNA, so as to realize the protective effect against NAFLD.
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BACKGROUND: Recent studies have demonstrated that sterol regulatory element binding protein-2 (SREBP-2) plays a key role in osteoarthritis, but its exact pathogenesis remains incompletely understood yet. OBJECTIVE:To investigate the expression of SREBP-2 in the process of interleukin-1β-induced articular chondrocyte degenerationin vitro. METHODS: Articular chondrocytes obtained from C57BL/6J mice were culturedin vitro. After the second passage, cels were randomly divided into four groups: control group, and three experimental groups treated with 10 μg/L interleukin-1β for 24, 48 and 72 hours, respectively. RESULTS AND CONCLUSION:The cels became hypertrophic after being stimulated by interleukin-1β, and the staining of colagen X was positive at 72 hours. MTT assay demonstrated that the cel activity after stimulation with interleukin-1β decreased with time. Results of RT-PCR showed that the expression of SREBP-2 and SREBP cleavage activating protein mRNA was significantly increased after stimulation with interleukin-1βas compared with the control group and increased with time. On the contrary, the expression of aggrecan and colagen II mRNA was decreased with time. It is revealed that interleukin-1β could inhibit the proliferation of regular chondrocytes and the expression of its extracelular matrix, and furthermore, induce chondrocyte hypertrophy. The expression of SREBP-2 showed a negative relationship with key cartilage genes during this interleukin-1β-induced degeneration.
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Objective To study the dynamic changes of injury and apoptosis of liver induced by lipid metabolic disturbance in the rats with diabetes mellitus and their correlation with the expressions of sterol regulatory element binding protein-1c(SREBP-1c)and c-Jun N-terminal kinase(JNK).Methods Experimental animals were randomly divided into 4 groups:diabetesgroup(n=64)induced by high-carbohydrate and high-fat diet plus intra-peritoneal streptozeotocin(STZ)injection,normal control(n=37)fed regular diet and receiving citric buffer solution injection,STZ group(n=42)fed regular diet and receiving STZ injection,high gluaxeard fat group(n =37)receiving citric buffer solution injection.Body weight,liver weight,fasting plasma glucose(FPG),fasting insulin(FINS),triglyceride(TG),total cholesterole(TC),alanine transaminase(ALT),asparate transaminase(AST)were detected at various time intervals.The changes of liver histopathology and ultrastructure were observed by ES and Sudan Ⅲ stanings,transmission electrom microscope.The expressions of SREBP-1c and JNK mRNAs and proteins were determined by real time-PCR methods.Apoptosis was analyzed by flow cytometry.Results The diabetic rats showed much lower body weight(P＜0.05)and higher liver weight than controls,STZ group and high-carbohydrate and fat group(P＜0.05),while showed higher levels(P＜0.05)of serum FPG,FINS,TG,TC,ALT,AST.Diabetic rats exhibited fatty degeneration of liver cells accompanied by inflammatory infiltration and fibrosis.Organelle structures were more disturbed and apoptosis was more obviou along with longer course of disease.The expressions of SREBP-1c,JNK proteins and mRNA were significantly enhanced.The rats fed high-carbohydrate and fat diet also showed similar liver lesions and enhanced SREBP-1c,J NK proteins and mRNA expressions but not as severe as in diabetes group Conclusions Insulin resistance and high blood glucose may induce diabetic hepatopathy.The high expressions of JNK and SREBP-1c may play important roles in liver lipid metabolism disorders and cell apoptosis.
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Nonalcoholic fatty liver(NAFL)is characterized by the hepatocyte steatosis and lipid accumulation,and is a clinical syndrome of unrelated to excessive alcohol consumption. At present,patients with the syndrome obviously increase in the whole world. Sterol regulatory element-binding proteins (SREBPs) are the key transcription factors of controlling the biosynthesis of cholesterol,fatty acids and triglycerides,and adipocyte differentiation. In this paper,the regulation of SREBPs and its research progress in the development of NAFL were reviewed.