RESUMO
BACKGROUND: Low-density lipoprotein receptor-related protein 1 (LRP1) plays a key role in fatty acid metabolism and glucose homeostasis. In the context of dyslipemia, LRP1 is upregulated in the heart. Our aim was to evaluate the impact of cardiomyocyte LRP1 deficiency on high fat diet (HFD)-induced cardiac and metabolic alterations, and to explore the potential mechanisms involved. METHODS: We used TnT-iCre transgenic mice with thoroughly tested suitability to delete genes exclusively in cardiomyocytes to generate an experimental mouse model with conditional Lrp1 deficiency in cardiomyocytes (TNT-iCre+-LRP1flox/flox). FINDINGS: Mice with Lrp1-deficient cardiomyocytes (cm-Lrp1-/-) have a normal cardiac function combined with a favorable metabolic phenotype against HFD-induced glucose intolerance and obesity. Glucose intolerance protection was linked to higher hepatic fatty acid oxidation (FAO), lower liver steatosis and increased whole-body energy expenditure. Proteomic studies of the heart revealed decreased levels of cardiac pro-atrial natriuretic peptide (pro-ANP), which was parallel to higher ANP circulating levels. cm-Lrp1-/- mice showed ANP signaling activation that was linked to increased fatty acid (FA) uptake and increased AMPK/ ACC phosphorylation in the liver. Natriuretic peptide receptor A (NPR-A) antagonist completely abolished ANP signaling and metabolic protection in cm-Lrp1-/- mice. CONCLUSIONS: These results indicate that an ANP-dependent axis controlled by cardiac LRP1 levels modulates AMPK activity in the liver, energy homeostasis and whole-body metabolism.
Assuntos
Resistência à Insulina/genética , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Miócitos Cardíacos/metabolismo , Obesidade/genética , Adenilato Quinase/metabolismo , Animais , Fator Natriurético Atrial/metabolismo , Células Cultivadas , Dieta Hiperlipídica , Intolerância à Glucose/genética , Intolerância à Glucose/metabolismo , Intolerância à Glucose/patologia , Metabolismo dos Lipídeos/genética , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/deficiência , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Camundongos Transgênicos , Miócitos Cardíacos/patologia , Obesidade/metabolismo , Obesidade/patologiaRESUMO
Human hepatic lipase (hHL) is mainly localized on the hepatocyte cell surface where it hydrolyzes lipids from remnant lipoproteins and high density lipoproteins and promotes their hepatic selective uptake. Furthermore, hepatic lipase (HL) is closely associated with obesity in multiple studies. Therefore, HL may play a key role on lipid homeostasis in liver and white adipose tissue (WAT). In the present study, we aimed to evaluate the effects of hHL expression on hepatic and white adipose triglyceride metabolism in vivo. Experiments were carried out in hHL transgenic and wild-type mice fed a Western-type diet. Triglyceride metabolism studies included ß-oxidation and de novo lipogenesis in liver and WAT, hepatic triglyceride secretion, and adipose lipoprotein lipase (LPL)-mediated free fatty acid (FFA) lipolysis and influx. The expression of hHL promoted hepatic triglyceride accumulation and de novo lipogenesis without affecting triglyceride secretion, and this was associated with an upregulation of Srebf1 as well as the main genes controlling the synthesis of fatty acids. Transgenic mice also exhibited more adiposity and an increased LPL-mediated FFA influx into the WAT without affecting glucose tolerance. Our results demonstrate that hHL promoted hepatic steatosis in mice mainly by upregulating de novo lipogenesis. HL also upregulated WAT LPL and promoted triglyceride-rich lipoprotein hydrolysis and adipose FFA uptake. These data support the important role of hHL in regulating hepatic lipid homeostasis and confirm the broad cardiometabolic role of HL.
Assuntos
Fígado Gorduroso/genética , Lipase/genética , Obesidade/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/patologia , Animais , Dieta Ocidental , Ácidos Graxos/metabolismo , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Regulação Enzimológica da Expressão Gênica , Glucose/metabolismo , Humanos , Lipase/biossíntese , Metabolismo dos Lipídeos/genética , Lipogênese/genética , Lipólise/genética , Camundongos , Camundongos Transgênicos , Obesidade/metabolismo , Obesidade/patologiaRESUMO
Apolipoprotein (apo) A-II has been biochemically and genetically linked to familial combined hyperlipidemia. Human ApoA-II transgenic mice and peroxisome proliferator-activated receptor alpha (PPARalpha)-deficient mice share some similar phenotypic characteristics. The aim of this study was to determine whether a fibrate-induced PPARalpha activation corrects the combined hyperlipidemia present in human apoA-II transgenic mice. ApoA-II transgenic mice were treated with fenofibrate (250 mg/kg) for 13 days. After this period, they presented a remarkable 8-fold increase in plasma triglycerides. This was concomitant with a 4-fold increase in non-high-density lipoprotein (non-HDL) cholesterol, a quantitatively similar decrease in HDL cholesterol and a severe reduction in mouse plasma apoA-I and apoA-II. Fenofibrate stimulated liver fatty acid beta-oxidation, increased the transcriptional expression of carnitine palmitoyltransferase 1 and phospholipid transfer protein, and decreased expression of apoA-I and apoC-III. However, very-low-density lipoprotein (VLDL)-triglyceride production and lipoprotein lipase (LPL) activities and the expression of other PPARalpha target genes were similar in mice treated with vehicle and fenofibrate. Further, fenofibrate-treated mice presented decreased in vivo [3H]VLDL catabolism and decreased VLDL-triglyceride hydrolysis by exogenous LPL. Therefore, the paradoxical enhancement of hyperlipidemia in fenofibrate-treated apoA-II transgenic mice is mainly due to decreased VLDL catabolism and, also, to a partial impairment in PPARalpha-signaling.