RESUMO
Mutations in apolipoprotein A5 (APOA5) have been associated with hypertriglyceridemia in humans and mice. This has been attributed to a stimulating role for APOA5 in lipoprotein lipase-mediated triglyceride hydrolysis and hepatic clearance of lipoprotein remnant particles. However, because of the low APOA5 plasma abundance, we investigated an additional signaling role for APOA5 in high-fat diet (HFD)-induced obesity. Wild-type (WT) and Apoa5(-/-) mice fed a chow diet showed no difference in body weight or 24-h food intake (Apoa5(-/-), 4.5±0.6 g; WT, 4.2±0.5 g), while Apoa5(-/-) mice fed an HFD ate more in 24 h (Apoa5(-/-), 2.8±0.4 g; WT, 2.5±0.3 g, P<0.05) and became more obese than WT mice. Also, intravenous injection of APOA5-loaded VLDL-like particles lowered food intake (VLDL control, 0.26±0.04 g; VLDL+APOA5, 0.11±0.07 g, P<0.01). In addition, the HFD-induced hyperphagia of Apoa5(-/-) mice was prevented by adenovirus-mediated hepatic overexpression of APOA5. Finally, intracerebroventricular injection of APOA5 reduced food intake compared to injection of the same mouse with artificial cerebral spinal fluid (0.40±0.11 g; APOA5, 0.23±0.08 g, P<0.01). These data indicate that the increased HFD-induced obesity of Apoa5(-/-) mice as compared to WT mice is at least partly explained by hyperphagia and that APOA5 plays a role in the central regulation of food intake.
Assuntos
Apolipoproteínas/deficiência , Dieta Hiperlipídica/efeitos adversos , Ingestão de Alimentos/fisiologia , Obesidade/fisiopatologia , Animais , Apolipoproteína A-V , Apolipoproteínas/administração & dosagem , Apolipoproteínas/genética , Calorimetria , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/genética , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Hiperlipidemias/etiologia , Hiperlipidemias/genética , Hiperlipidemias/metabolismo , Hiperfagia/etiologia , Hiperfagia/genética , Hiperfagia/metabolismo , Injeções Intravenosas , Injeções Intraventriculares , Resistência à Insulina/genética , Resistência à Insulina/fisiologia , Lipídeos/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/etiologia , Obesidade/genéticaRESUMO
The assignment of causative genes to noncoding variants identified in genome-wide association studies (GWASs) is challenging. We show how combination of knowledge from gene and pathway databases and chromatin interaction data leads to reinterpretation of published quantitative trait loci for blood metabolites. We describe a previously unidentified link between the rs2403254 locus, which is associated with the ratio of 3-methyl-2-oxobutanoate and alpha-hydroxyisovalerate levels, and the distal LDHA gene. We confirmed that lactate dehydrogenase can catalyze the conversion between these metabolites in vitro, suggesting that it has a role in branched-chain amino acid metabolism. Examining datasets from the ENCODE project we found evidence that the locus and LDHA promoter physically interact, showing that LDHA expression is likely under control of distal regulatory elements. Importantly, this discovery demonstrates that bioinformatic workflows for data integration can have a vital role in the interpretation of GWAS results.