RESUMO
Non-alcoholic fatty liver disease (NAFLD) presents with growing prevalence worldwide, though its pharmacological treatment remains to be established. This study aimed to evaluate the effects of a PPAR-alpha agonist on liver tissue structure, ultrastructure, and metabolism, focusing on gene and protein expression of de novo lipogenesis and gluconeogenesis pathways, in diet-induced obese mice. Male C57BL/6 mice (three months old) received a control diet (C, 10% of lipids, n = 10) or a high-fat diet (HFD, 50% of lipids, n = 10) for ten weeks. These groups were subdivided to receive the treatment (n = 5 per group): C, C-alpha (PPAR-alpha agonist, 2.5 mg/kg/day mixed in the control diet), HFD and HFD-alpha group (PPAR-alpha agonist, 2.5 mg/kg/day mixed in the HFD). The effects were compared with biometrical, biochemical, molecular biology and transmission electron microscopy (TEM) analyses. HFD showed greater body mass (BM) and insulinemia than C, both of which were tackled by the treatment in the HFD-alpha group. Increased hepatic protein expression of glucose-6-phosphatase, CHREBP and gene expression of PEPCK in HFD points to increased gluconeogenesis. Treatment rescued these parameters in the HFD-alpha group, eliciting a reduced hepatic glucose output, confirmed by the smaller GLUT2 expression in HFD-alpha than in HFD. Conversely, favored de novo lipogenesis was found in the HFD group by the increased expression of PPAR-gamma, and its target gene SREBP-1, FAS and GK when compared to C. The treatment yielded a marked reduction in the expression of all lipogenic factors. TEM analyses showed a greater numerical density of mitochondria per area of tissue in treated than in untreated groups, suggesting an increase in beta-oxidation and the consequent NAFLD control. PPAR-alpha activation reduced BM and treated insulin resistance (IR) and NAFLD by increasing the number of mitochondria and reducing hepatic gluconeogenesis and de novo lipogenesis protein and gene expressions in a murine obesity model.
Assuntos
Gorduras na Dieta/efeitos adversos , Fígado/metabolismo , Mitocôndrias Hepáticas/metabolismo , Obesidade/tratamento farmacológico , PPAR alfa/agonistas , Pirimidinas/farmacologia , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos , Gorduras na Dieta/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose-6-Fosfatase/biossíntese , Resistência à Insulina , Lipogênese/efeitos dos fármacos , Fígado/patologia , Masculino , Camundongos , Mitocôndrias Hepáticas/patologia , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Proteínas Nucleares/biossíntese , Obesidade/induzido quimicamente , Obesidade/metabolismo , Obesidade/patologia , PPAR alfa/metabolismo , PPAR gama/biossíntese , Fosfoenolpiruvato Carboxiquinase (ATP)/biossíntese , Proteína de Ligação a Elemento Regulador de Esterol 1/biossíntese , Fatores de Transcrição/biossíntese , Receptor fas/biossínteseRESUMO
The aim of the present study was to evaluate the effects of ST (rosuvastatin) and GZ (rosiglitazone) on IR (insulin resistance) and on liver as well as adipose tissue in mice fed on an HF (high-fat) diet. Our data show that treatment with ST resulted in a marked improvement in insulin sensitivity characterized by enhanced glucose clearance during the insulin tolerance test and a 70% decrease in the HOMA-IR (homoeostasis model assessment of insulin resistance) index level (P=0.0008). The ST-treated mice exhibited lower gains in BM (body mass; -8%; P<0.01) and visceral fat pad thickness (-60%; P<0.01) compared with the untreated HF group. In comparison with HF-diet-fed mice, HF+ST-treated mice showed a significant reduction in hepatomegaly and liver steatosis (-6%, P<0.05; and -21%, P<0.01 respectively). In HF+ST-treated mice, the hepatic TAG (triacylglycerol) levels were reduced by 58% compared with the HF group (P<0.01). In addition, the expression of SREBP-1c (sterol-regulatory-element-binding protein-1c) was decreased by 50% in the livers of HF+ST-treated mice (P<0.01) relative to the HF-diet-fed mice. The levels of resistin were lower in the HF+ST-treated group compared with the HF group (44% less, P< 0.01). In conclusion, we demonstrated that ST treatment improved insulin sensitivity and decreased liver steatosis in mice fed on an HF diet. Furthermore, ST reduced BM gains, improved the circulating levels of plasma cholesterol and TAG, and reduced hepatic TAG, which was concomitant with lower resistin levels.
Assuntos
Adiposidade/efeitos dos fármacos , Fígado Gorduroso/prevenção & controle , Fluorbenzenos/uso terapêutico , Resistência à Insulina/fisiologia , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Adipocinas/metabolismo , Tecido Adiposo/efeitos dos fármacos , Animais , Glicemia/metabolismo , Composição Corporal/efeitos dos fármacos , Dieta Hiperlipídica , Homeostase , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Hepatopatia Gordurosa não Alcoólica , Resistina/sangue , Rosiglitazona , Rosuvastatina Cálcica , Proteína de Ligação a Elemento Regulador de Esterol 1/biossíntese , Tiazolidinedionas/uso terapêutico , Triglicerídeos/sangue , Triglicerídeos/metabolismoRESUMO
INTRODUCTION: Triglyceride accumulation in the liver is an early feature in the development of nonalcoholic fatty liver disease (NAFLD) associated with human obesity, which is a multifactorial syndrome and whose underlying mechanisms are beginning to be understood. OBJECTIVES: Liver peroxisome proliferator-activated receptor-γ (PPAR-γ) mRNA expression was measured as a signaling mechanism related to steatosis in obese patients with NAFLD. METHODS: Liver PPAR-γ and sterol receptor element-binding protein 1c (SREBP-1c) mRNA (real-time RT-PCR), serum total adiponectin (RIA), and high molecular weight (HMW)-adiponectin (ELISA) levels, and insulin resistance (IR) evolution (homeostasis model assessment-IR) were determined in 22 obese NAFLD patients (16 with steatosis and six with steatohepatitis) who underwent subtotal gastrectomy with gastrojejunal anastomosis in Roux-en-Y and 16 nonobese subjects who underwent laparoscopic cholecystectomy (controls). RESULTS: Liver PPAR-γ mRNA levels were 112 and 188% higher (P < 0.05) than control values in obese patients with steatosis and steatohepatitis, respectively, who also exhibited 70 and 62% increases in those of SREBP-1c, concomitantly with IR and lower levels of serum total adiponectin and HMW-adiponectin (P < 0.05). Liver PPAR-γ expression showed positive associations with SREBP-1c mRNA levels (r = 0.86; P < 0.0001), serum insulin levels (r = 0.39; P < 0.01), and homeostasis model assessment-IR (r = 0.60; P < 0.0001), and negative correlations with total adiponectin (r = -0.37; P < 0.01) and HMW-adiponectin (r = -0.51; P < 0.001) levels in serum. CONCLUSIONS: PPAR-γ is up-regulated in the liver of obese patients with NAFLD, representing an additional reinforcing lipogenic mechanism to SREBP-1c induction in the development of hepatic steatosis.
Assuntos
Fígado/metabolismo , Obesidade/metabolismo , PPAR gama/biossíntese , Proteína de Ligação a Elemento Regulador de Esterol 1/biossíntese , Adiponectina/biossíntese , Adiponectina/sangue , Adulto , Anastomose em-Y de Roux , Fígado Gorduroso/metabolismo , Feminino , Humanos , Resistência à Insulina/fisiologia , Masculino , Peso Molecular , Obesidade/cirurgia , RNA Mensageiro/biossíntese , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
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.