Proinflammatory gene expression and renal lipogenesis are modulated by dietary protein content in obese Zucker fa/fa rats

Obesity is a risk factor for the development of chronic kidney disease (CKD) and end-stage renal disease. It is not clear whether the adoption of a high-protein diet in obese patients affects renal lipid metabolism or kidney function. Thus the aims of this study were to assess in obese Zuckerfa/fa rats the effects of different types and amounts of dietary protein on the expression of lipogenic and inflammatory genes, as well as renal lipid concentration and biochemical parameters of kidney function. Rats were fed different concentrations of soy protein or casein (20, 30, 45%) for 2 mo. Independent of the type of protein ingested, higher dietary protein intake led to higher serum triglycerides (TG) than rats fed adequate concentrations of protein. Additionally, the soy protein diet significantly increased serum TG compared with the casein diet. However, rats fed soy protein had significantly decreased serum cholesterol concentrations compared with those fed a casein diet. No significant differences in renal TG and cholesterol concentrations were observed between rats fed with either protein diets. Renal expression of sterol-regulatory element binding protein 2 (SREBP-2) and its target gene HMG-CoA reductase was significantly increased as the concentration of dietary protein increased. The highest protein diets were associated with greater expression of proinflammatory cytokines in the kidney, independent of the type of dietary protein. These results indicate that high soy or casein protein diets upregulate the expression of lipogenic and proinflammatory genes in the kidney.     

Effects of Lactobacillus Fermented Soymilk and Soy Yogurt on Hepatic Lipid Accumulation in Rats Fed a Cholesterol-Free Diet

We examined the effects of lactic acid fermented soymilk, in which part of the soymilk was replaced with okara (soy yogurt), on plasma and hepatic lipid profiles in rats fed a cholesterol-free diet. Additionally, we investigated the effects of soy yogurt on hepatic gene expression in rats using DNA microarray analysis. Male Sprague-Dawley rats aged 5 weeks (n=5/group) were fed a control diet (AIN-93) or a test diet in which 20% of the diet was replaced by soy yogurt for 7 weeks. Soy yogurt consumption did not affect body weight or adipose tissue weight as compared with control diet. In the soy yogurt group, the liver weight and hepatic triglyceride content were significantly lower than the control group, and the level of plasma cholesterol was also lower. Furthermore, DNA microarray analysis indicated that soy yogurt ingestion down-regulated the expression of the SREBP-1 gene and enzymes related to lipogenesis in the rat liver, while expression of β-oxidation-related genes was up-regulated. These results suggest that soy yogurt is beneficial in preventing hepatic lipid accumulation in rats.     

Dietary soy protein induces hepatic lipogenic enzyme gene expression while suppressing hepatosteatosis in obese female Zucker rats bearing DMBA-initiated mammary tumors

Fatty liver is associated with obesity and breast cancer. We used an obese rat model of mammary cancer to examine whether hepatosteatosis is modifiable by diet and associated with altered expression of hepatic lipogenic enzyme genes, thyroid hormone system genes and cholesterol metabolism-related genes. Beginning at the age of 5 weeks, lean and obese female Zucker rats were fed high-isoflavone soy protein- or casein (control protein)-containing diets. Rats were euthanized at 200 days of age [corresponding to 147 days after administration of carcinogen to induce mammary tumors; (Hakkak et al. in, Oncol Lett 2:29–36, 2011)]. Obese rats had a greater degree of liver steatosis than lean rats. Obese casein-fed rats had marked steatosis with small foci of mononuclear infiltration, whereas obese soy protein-fed rats had a significantly lower steatosis index. Comparisons between lean and obese casein-fed rats showed that obesity was associated with significant reductions in hepatic mRNA abundance for Glucose 6-Phosphate Dehydrogenase (G6PD), 6-Phosphogluconate Dehydrogenase (6PGD), Thyroid Receptor Alpha 1 (TRα1), Thyroid Receptor Beta 1 (TRβ1) and Iodothyronine Deiodinase 1 (DIO1). The soy protein diet was associated with increased expression of Fatty Acid Synthase (FASN), Malic Enzyme 1 (ME1), 6PGD, Sterol Regulatory Element Binding Protein-1c (SREBP-1c) and SREBP-2 genes in the livers of obese but not lean rats. Western blot analysis showed a significant induction of ME1 protein expression in the livers of obese, soy protein-fed rats, which paralleled the increased serum insulin level in this group. Long-term soy protein consumption can counter hepatic steatosis while coincidently promoting hepatic lipogenic gene expression, the latter likely a consequence of elevated serum insulin. We suggest that elevations in serum insulin, hepatic lipogenesis and cholesterol synthesis all contributed to the increased tumorigenesis previously observed for the obese, soy protein-fed rats.     

Isoflavone-poor soy protein alters the lipid metabolism of rats by SREBP-mediated down-regulation of hepatic genes

Soy intake acts hypolipidemically. Besides isoflavones, soy protein itself is suggested to influence plasma lipid concentrations. We investigated the effects of an alcohol-washed isoflavone-poor soy protein isolate on plasma and liver lipids and the hepatic expression of genes encoding proteins involved in cholesterol and fatty acid metabolism. Therefore, rats were fed diets containing 200 g/kg of either ethanol-extracted soy protein isolate or casein over 22 days. Rats fed soy protein isolate had markedly lower concentrations of liver cholesterol and lower concentrations of triglycerides in the liver and in plasma than rats fed casein (P<.05). Rats fed soy protein isolate had lower relative mRNA concentrations of sterol-regulatory element-binding protein (SREBP)-2, 3-hydroxy-3-methylglutaryl coenzyme A reductase, low-density lipoprotein receptor, cholesterol 7alpha-hydroxylase, apolipoprotein B, Delta9-desaturase and glucose-6-phosphate dehydrogenase in the liver than rats fed casein (P<.05). Hepatic mRNA concentration of SREBP-1c tended to be lower in rats fed soy protein isolate (P<.10). Hepatic mRNA concentrations of insulin-induced gene (Insig) 1 and Insig-2 and of microsomal triglyceride transfer protein, as well as plasma concentrations of free fatty acids, insulin and glucagon, were not different between the two groups. In conclusion, this study suggests that isoflavone-poor soy protein isolate affects cellular lipid homeostasis by the down-regulation of SREBPs and its target genes in the liver, which are involved in the synthesis of cholesterol and triglycerides.     

Effect of Octreotide on Hepatic Steatosis in Diet-Induced Obesity in Rats

Background

Non-alcoholic fatty liver disease (NAFLD) caused by liver lipid dysregulation is linked to obesity. Somatostatin (SST) and its analogs have been used to treat pediatric hypothalamic obesity. However, the application of such drugs for the treatment of NAFLD has not been evaluated.

Objective

This study aimed to investigate the expression levels of important regulators of hepatic lipid metabolism and the possible effect of the SST analog octreotide on these regulators.

Methods

SD rats were assigned to a control group and a high-fat diet group. Obese rats from the high-fat diet group were further divided into the obese and octreotide-treated groups. The body weight, plasma SST, fasting plasma glucose (FPG), insulin, triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and free fatty acid (FFA) levels were measured. Hepatic steatosis was evaluated based on the liver TG content, HE staining and oil red O staining. The SREBP-1c, ACC1, FAS, MTP, apoB and ADRP expression levels in the liver were also determined by RT-PCR, qRT-PCR, western blot or ELISA.

Results

The obese rats induced by high-fat diet expressed more SREBP-1c, FAS and ADRP but less MTP protein in the liver than those of control rats, whereas octreotide intervention reversed these changes and increased the level of apoB protein. Compared to the control group, obese rats showed increased liver ACC1, SREBP-1c and apoB mRNA levels, whereas octreotide-treated rats showed decreased mRNA levels of apoB and SREBP-1c. This was accompanied by increased body weight, liver TG contents, FPG, TG, TC, LDL-C, FFA, insulin and derived homeostatic model assessment (HOMA) values. Octreotide intervention significantly decreased these parameters. Compared to the control group, the obese group showed a decreasing trend on plasma SST levels, which were significantly increased by the octreotide intervention.

Conclusion

Octreotide can ameliorate hepatic steatosis in obese rats, possibly by decreasing hepatic lipogenesis and increasing TG export from hepatocytes.     

Effect of an enriched cholesterol diet during gestation on fatty acid synthase, HMG-CoA reductase and SREBP-1/2 expressions in rabbits

Pregnancy is associated with hyperlipidemia and hypercholesterolemia in humans. These changes take place to support fetal growth and development, and modifications of these maternal concentrations may influence lipids and cholesterol synthesis in the dam, fetus and placenta. Administration of a 0.2% enriched cholesterol diet (ECD) during rabbit gestation significantly increased cholesterol and triglyceride (TG) levels in maternal livers and decreased fetal weight by 15%. Here we used Western blot analysis to examine the impact of gestation and 0.2% ECD on the expression levels of fatty acid synthase (FAS), HMGR and SREBP-1/2, which are involved in either lipid or cholesterol synthesis. We confirmed that gestation modifies the hepatic and circulating lipid profile in the mother. Our data also suggest that the maternal liver mainly supports lipogenesis, while the placenta plays a key role in cholesterol synthesis. Thus, our data demonstrate a decrease in HMGR protein levels in dam livers by feeding an ECD. In the placenta, SREBPs are highly expressed, and the ECD supplementation increased nuclear SREBP-1/2 protein levels. In addition, our results show a decrease in FAS protein levels in non-pregnant liver and in the liver of offspring from ECD-treated animals. Finally, our data suggest that the placenta does not modify its own cholesterol synthesis in response to an increase in circulating cholesterol. However, the dam liver compensates for this increase by essentially decreasing the level of HMGR expression. Because HMGR and FAS expressions do not correlate with the circulating lipid profile, it would be interesting to find which genes are then targeted by SREBP-1/2 during gestation.     

SREBP-1c in nonalcoholic fatty liver disease induced by Western-type high-fat diet plus fructose in rats

This study concentrated on the initial events triggering the development of nonalcoholic fatty liver disease induced by a high-fat plus fructose (HF-F) diet and on the possibility of delaying nonalcoholic fatty liver disease progression by adding dehydroepiandrosterone (DHEA) to the diet. Sterol regulatory element binding protein-1c (SREBP-1c) activation plays a crucial role in the progression of nonalcoholic fatty liver disease induced by an HF-F diet. This study investigated the protective effects of DHEA, a compound of physiological origin with multitargeted antioxidant properties, against the induction of SREBP-1c and on liver insulin resistance in rats fed an HF-F diet, which mimics a typical unhealthy Western diet. An HF-F diet, fortified or not with DHEA (0.01%, w/w), was administered for 15 weeks to male Wistar rats. After HF-F the liver showed unbalanced oxidative status, fatty infiltration, hepatic insulin resistance, and inflammation. The addition of DHEA to the diet reduced both activation of oxidative-stress-dependent pathways and expression of SREBP-1c and partially restored the expression of liver X-activated receptor-α and insulin receptor substrate-2 genes. DHEA supplementation of the HF-F diet reduced de novo lipogenesis and delayed progression of nonalcoholic fatty liver disease, demonstrating a relationship between oxidative stress and nonalcoholic fatty liver disease via SREBP-1c.     

Effects of soy protein and isoflavone on hepatic fatty acid synthesis and oxidation and mRNA expression of uncoupling proteins and peroxisome proliferator-activated receptor gamma in adipose tissues of rats

Soy protein rich in isoflavones profoundly affects lipid metabolism in experimental animals. To distinguish the roles of the protein and isoflavone components of a soy protein preparation in regulating lipid metabolism, we compared the effects of diets containing methanol-washed soy protein low in isoflavone supplemented with a 0-, 0.5- and 4-g/kg isoflavone preparation on hepatic fatty acid metabolism and adipose tissue gene expression in rats. Diets containing soy protein irrespective of the isoflavone levels decreased the activities and mRNA expression of enzymes involved in hepatic fatty acid synthesis to similar levels. Methanol-washed soy protein compared to casein increased the mRNA expression of peroxisome proliferator-activated receptor (PPAR) alpha, and supplementing the soy protein diet with isoflavone further increased this parameter dose-dependently. However, methanol-washed soy protein compared to casein was totally ineffective in altering the activities and mRNA levels of enzymes involved in fatty acid oxidation. Supplementation of soy protein diets with isoflavone slightly increased these parameters. The mRNA level of uncoupling protein (UCP) 1 in brown adipose tissue was significantly increased and mRNA levels of UCP2 and 3, and PPARgamma2 tended to be higher in rats fed methanol-washed soy protein not supplemented with isoflavone than in the animals fed casein. Adding isoflavone to the soy protein diets dose-dependently increased these parameters. These results suggested that the protein rather than isoflavone component is primarily responsible for the physiological activity of soy protein rich in isoflavones in reducing hepatic lipogenesis. However, isoflavones may have a role in regulating heptic fatty acid oxidation and adipose tissue gene expression.     

The role of dietary protein on lipotoxicity

Lipotoxicity is a metabolic abnormality frequently observed during the development of obesity and is the main cause of several changes in the metabolic observed during metabolic syndrome. Consistent consumption of diets high in saturated fat or simple carbohydrates combined with low physical activity are the main causes of obesity and its comorbidities. However, the contribution of dietary protein and, in particular, the contribution due to the type of dietary protein, to the process of obesity and its metabolic consequences are less well-understood. In this review, we showed that the type of dietary protein has a significant contribution to the process of lipotoxicity through the modulation of insulin secretion and the regulation of adipocyte metabolic function. Consumption of soy protein stimulates insulin secretion to a lower extent than casein despite the fact that both are high-quality proteins. The amino acid profiles of soy protein and its isoflavones are responsible for the reduced insulin secretion. Also, soy protein increases insulin sensitivity, whereas casein has the opposite effect. Consequently, soy protein reduces SREBP-1 expression in the liver leading to low accumulation of hepatic triglycerides, despite the consumption of a high-fat diet. Furthermore, soy protein reduces adipocyte hypertrophy, hyperleptinemia, and free fatty acid concentration. Thus, the influx of FA into the liver decreases, and hepatic oxidation of FA increases. These metabolic changes result in a decrease in lipid depots and ceramide which reduce hepatic lipotoxicity, whereas casein produces the opposite effect. This study emphasizes that the type of dietary protein has an important effect on lipotoxicity.     

The critical role of atypical protein kinase C in activating hepatic SREBP-1c and NF��B in obesity

Obesity is frequently associated with systemic insulin resistance, glucose intolerance, and hyperlipidemia. Impaired insulin action in muscle and paradoxical diet/insulin-dependent overproduction of hepatic lipids are important components of obesity, but their pathogenesis and inter-relationships between muscle and liver are uncertain. We studied two murine obesity models, moderate high-fat-feeding and heterozygous muscle-specific PKC-λ knockout, in both of which insulin activation of atypical protein kinase C (aPKC) is impaired in muscle, but conserved in liver. In both models, activation of hepatic sterol receptor element binding protein-1c (SREBP-1c) and NFκB (nuclear factor-kappa B), major regulators of hepatic lipid synthesis and systemic insulin resistance, was chronically increased in the fed state. In support of a critical mediatory role of aPKC, in both models, inhibition of hepatic aPKC by adenovirally mediated expression of kinase-inactive aPKC markedly diminished diet/insulin-dependent activation of hepatic SREBP-1c and NFκB, and concomitantly improved hepatosteatosis, hypertriglyceridemia, hyperinsulinemia, and hyperglycemia. Moreover, in high-fat–fed mice, impaired insulin signaling to IRS-1–dependent phosphatidylinositol 3-kinase, PKB/Akt and aPKC in muscle and hyperinsulinemia were largely reversed. In obesity, conserved hepatic aPKC-dependent activation of SREBP-1c and NFκB contributes importantly to the development of hepatic lipogenesis, hyperlipidemia, and systemic insulin resistance. Accordingly, hepatic aPKC is a potential target for treating obesity-associated abnormalities.     

Activation of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase during high fat diet feeding

The liver plays a central role in regulating cholesterol homeostasis. High fat diets have been shown to induce obesity and hyperlipidemia. Despite considerable advances in our understanding of cholesterol metabolism, the regulation of liver cholesterol biosynthesis in response to high fat diet feeding has not been fully addressed. The aim of the present study was to investigate mechanisms by which a high fat diet caused activation of liver 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) leading to increased cholesterol biosynthesis. Mice were fed a high fat diet (60% kcal fat) for 5 weeks. High fat diet feeding induced weight gain and elevated lipid levels (total cholesterol and triglyceride) in both the liver and serum. Despite cholesterol accumulation in the liver, there was a significant increase in hepatic HMG-CoA reductase mRNA and protein expression as well as enzyme activity. The DNA binding activity of sterol regulatory element binding protein (SREBP)-2 and specific protein 1 (Sp1) were also increased in the liver of mice fed a high fat diet. To validate the in vivo findings, HepG2 cells were treated with palmitic acid. Such a treatment activated SREBP-2 as well as increased the mRNA and enzyme activity of HMG-CoA reductase leading to intracellular cholesterol accumulation. Inhibition of Sp1 by siRNA transfection abolished palmitic acid-induced SREBP-2 and HMG-CoA reductase mRNA expression. These results suggest that Sp1-mediated SREBP-2 activation contributes to high fat diet induced HMG-CoA reductase activation and increased cholesterol biosynthesis. This may play a role in liver cholesterol accumulation and hypercholesterolemia.     

Soy protein suppresses gene expression of acetyl-coA carboxylase alpha from promoter PI in rat liver

Dietary soy protein isolate (SPI) reduces hepatic lipogenesis by suppressing gene expression of lipogenic enzymes, including acetyl-CoA carboxylase (ACC). In order to elucidate the mechanism of this regulation, the effect of dietary SPI on promoter (PI and PII) specific gene expression of ACC alpha was investigated. Rats were fed experimental diets containing SPI or casein as a nitrogen source. SPI feeding decreased the hepatic contents of total ACC mRNA as well as triglyceride (TG) content, but dietary SPI affected the amount of sterol-regulatory element binding protein (SREBP)-1 mRNA and protein very little. The amount of ACC mRNA transcribed from PII promoter containing SRE was not significantly affected by dietary protein, while a significant decrease in PI-generated ACC mRNA content was observed in rats fed the SPI diet. These data suggest that SPI feeding decreased the hepatic contents of ACC alpha mRNA mainly by regulating PI promoter via a nuclear factor(s) other than SREBP-1.     

Regulatory effect of diosgenin on lipogenic genes expression in high-fat diet-induced obesity in mice

Obesity is one of the most serious health problems in the world, increasing the risk of other chronic diseases. Alterations in fatty acid synthesis related genes are crucially involved in obesity progression. Diosgenin (DG) was one of the phytosterols compounds with vital activity against lipid disorders. Therefore, this study was intended to evaluate the protective effect of DG on lipogenesis in the high-fat diet (HFD)-induced obesity in mice, via investigating the expression of two of the fatty acid synthesis–involved genes; sterol regulatory element-binding protein (SREBP-1c) and fatty acid synthase (FASN) genes. Thirty adult male mice were divided into 3 groups. Control group, fed with normal diet; HFD group, mice fed with a high-fat diet and HFD + DG group, mice fed with a high-fat diet and supplemented in parallel with DG for 6 consecutive weeks. The effect of DG on Body weights, liver enzymes, lipid profile, were evaluated. Histopathological fatty changes as well as SREBP-1c and FASN gene expression were also investigated. DG significantly alleviated body weight gain, adjusted liver enzymes, and improved lipid profile. Additionally, DG ameliorated the histopathological changes by reducing the lipid vacuoles and hence the hepatosteatosis. Accordingly, DG significantly downregulated the two-fold increase in the SREBP-1c and FASN gene expression observed in the HFD group. In conclusion, DG possesses a beneficial impact against diet-induced obesity in mice, which makes it a good candidate for NAFLD and obesity prevention.     

Increased Hepatic Lipogenesis Elevates Liver Cholesterol Content

Cardiovascular diseases (CVDs) are the most common cause of death in patients with nonalcoholic fatty liver disease (NAFLD) and dyslipidemia is considered at least partially responsible for the increased CVD risk in NAFLD patients. The aim of the present study is to understand how hepatic de novo lipogenesis influences hepatic cholesterol content as well as its effects on the plasma lipid levels. Hepatic lipogenesis was induced in mice by feeding a fat-free/high-sucrose (FF/HS) diet and the metabolic pathways associated with cholesterol were then analyzed. Both liver triglyceride and cholesterol contents were significantly increased in mice fed an FF/HS diet. Activation of fatty acid synthesis driven by the activation of sterol regulatory element binding protein (SREBP)-1c resulted in the increased liver triglycerides. The augmented cholesterol content in the liver could not be explained by an increased cholesterol synthesis, which was decreased by the FF/HS diet. HMG-CoA reductase protein level was decreased in mice fed an FF/HS diet. We found that the liver retained more cholesterol through a reduced excretion of bile acids, a reduced fecal cholesterol excretion, and an increased cholesterol uptake from plasma lipoproteins. Very low-density lipoprotein-triglyceride and -cholesterol secretion were increased in mice fed an FF/HS diet, which led to hypertriglyceridemia and hypercholesterolemia in Ldlr^-/- mice, a model that exhibits a more human like lipoprotein profile. These findings suggest that dietary cholesterol intake and cholesterol synthesis rates cannot only explain the hypercholesterolemia associated with NAFLD, and that the control of fatty acid synthesis should be considered for the management of dyslipidemia.     

Effect of phytate in soy protein on the serum and liver cholesterol levels and liver fatty acid profile in rats

Dietary soy protein, in comparison with casein, generally lowers the serum cholesterol concentration in rats fed on a cholesterol-enriched diet, while mixed results were observed in rats fed on a diet free of cholesterol. Soy protein also suppresses the conversion of linoleic acid to arachidonic acid in the rat liver. The present study examines whether phytate, a minor component of a soy protein isolate, is responsible for these beneficial effects of soy protein. Weanling male rats were fed for 4 weeks on a purified diet containing a 20% level of protein (either casein (CAS), soy protein (SOY), phytate-depleted SOY (PDSOY) or phytate-replenished PDSOY (PRSOY)) and cholesterol (0 or 0.5%). The dietary protein source and phytate level only affected the serum and liver cholesterol concentrations when the animals were fed on the cholesterol-enriched diet, being significantly lower in those rats fed on the SOY and PRSOY diets than in those fed on the CAS diet, while the concentrations in the rats fed on the PDSOY diet were intermediate. When the animals were fed on the cholesterol-free diet, the ratio of (20:3n-6 + 20:4n-6)/18:2n-6 in liver phosphatidylcholine, a delta6 desaturation index, was significantly lower in the SOY diet group than in the CAS, PDSOY and PRSOY diet groups. Dietary cholesterol significantly depressed the ratio, but neither depletion nor replenishment of phytate affected the ratio. These results suggest that phytate in soy protein played a limited role in the cholesterol-lowering effect of soy protein and was not involved in the metabolism of linoleic acid.     

Supplementation of orotic acid to the casein, but not to egg protein, soy protein, or wheat gluten diets, increases serum ornithine carbamoyltransferase activity

Effects of dietary supplementation of orotic acid to a diet containing the casein protein were compared with diets containing egg protein, soy protein, or wheat gluten on lipid levels in the liver and serum and activities of ornithine carbamoyltransferase (OCT) and alanine aminotransferase in the serum of rats. We found that supplementation of orotic acid to each diet increased the contents of the liver total lipids, triacylglycerol, and phospholipids compared with those not supplemented. The contents of liver total lipids, triacylglycerol, cholesterol, and phospholipids in rats fed the casein diet were significantly higher than those of rats fed the other three diets when orotic acid was supplemented. The levels of triacylglycerol, cholesterol, and phospholipids in the serum of rats fed the casein diet were markedly decreased by addition of orotic acid. The supplementation of orotic acid significantly increased the activities of both serum OCT and alanine aminotransferase in rats fed the casein diet, but not in rats fed the other diets. In conclusion, liver lipid accumulation induced by dietary orotic acid depends on the type of dietary protein. The enhancement of serum OCT activity may result from liver lipid accumulation in rats fed the casein diet supplemented with orotic acid, demonstrating hepatic damage.     

肥胖大鼠模型的建立及其脂代谢相关分子机制研究

目的建立饮食诱导的肥胖(diet-induced obesity,DIO)大鼠模型并初步探讨其发病的分子机制。方法用脂肪含量30%的高脂饲料饲喂雄性SD大鼠25周,观察大鼠体重、Lee’s指数、肝组织病理改变,检测大鼠空腹血糖及空腹血清胰岛素水平,并通过real-time PCR,检测成模大鼠肝脏中乙酰辅酶A羧化酶(ACC)、脂肪酸合酶(FAS)、激素敏感酯酶(HSL)以及固醇调节元件结合蛋白-1c(SREBP-1c)的表达变化。结果高脂饲料饲喂6周后,DIO组大鼠体重、Lee’s指数均显著增加;25周后肝脏脂肪异常蓄积,出现中重度脂肪肝,空腹血糖及胰岛素水平显著升高,出现明显的胰岛素抵抗。肝脏中ACC、FAS和HSL表达显著增加,SREBP-1c表达水平达到正常组的2.56倍,两组间差异极其显著。结论成功建立了DIO大鼠模型,通过检测脂代谢相关基因的表达水平,初步阐释了营养性肥胖的发生与脂代谢变化之间的关系,SREBP-1c,ACC,FAS和HSL参与了DIO的形成,从而初步揭示了脂代谢变化与营养性肥胖的发生的关系。     

LXRs regulate the balance between fat storage and oxidation

Despite the well-established role of liver X receptors (LXRs) in regulating cholesterol homeostasis, their contribution to lipid homeostasis remains unclear. Here we show that LXR null mice are defective in hepatic lipid metabolism and are resistant to obesity when challenged with a diet containing both high fat and cholesterol. This phenotype is dependent on the presence of dietary cholesterol and is accompanied by the aberrant production of thyroid hormone in liver. Interestingly, the inability of LXR-/- mice to induce SREBP-1c-dependent lipogenesis does not explain the LXR-/- phenotype, since SREBP-1c null mice are not obesity resistant. Instead, the LXR-/- response is due to abnormal energy dissipation resulting from uncoupled oxidative phosphorylation and ectopic expression of uncoupling proteins in muscle and white adipose. These studies suggest that, by selectively sensing the cholesterol component of a lipid-rich diet, LXRs govern the balance between storage and oxidation of dietary fat.