title: Hepatic lipase deficiency produces glucose intolerance, inflammation and hepatic steatosis.
abstract: Metabolic syndrome and type 2 diabetes mellitus constitute a major problem to global health, and their incidence is increasing at an alarming rate. Non-alcoholic fatty liver disease, which affects up to 90% of obese people and nearly 70% of the overweight, is commonly associated with MetS characteristics such as obesity, insulin resistance, hypertension and dyslipidemia. In the present study, we demonstrate that hepatic lipase (HL)-inactivation in mice fed with a high-fat, high-cholesterol diet produced dyslipidemia including hypercholesterolemia, hypertriglyceridemia and increased non-esterified fatty acid levels. These changes were accompanied by glucose intolerance, pancreatic and hepatic inflammation and steatosis. In addition, compared with WT mice, HL(-/-) mice exhibited enhanced circulating MCP1 levels, monocytosis and higher percentage of CD4+Th17+ cells. Consistent with increased inflammation, livers from HL(-/-) mice had augmented activation of the stress SAPK/JNK- and p38-pathways compared with the activation levels of the kinases in livers from WT mice. Analysis of HL(-/-) and WT mice fed regular chow diet showed dyslipidemia and glucose intolerance in HL(-/-) mice without any other changes in inflammation or hepatic steatosis. Altogether, these results indicate that dyslipidemia induced by HL-deficiency in combination with a high-fat, high-cholesterol diet promotes hepatic steatosis and inflammation in mice which are, at least in part, mediated by the activation of the stress SAPK/JNK- and p38-pathways. Future studies are warranted to asses the viability of therapeutic strategies based on the modulation of these kinases to reduce hepatic steatosis associated to lipase dysfunction.
authors.affiliation: Institute of Health Research-INCLIVAAvenida Menéndez Pelayo, 4, 46010 Valencia, SpainEndocrinology and Nutrition Department Clinic Hospital and Department of MedicineUniversity of Valencia, Valencia, SpainCIBER de Diabetes y Enfermedades Metabólicas asociadas (CIBERDEM)Valencia, SpainDepartment of FarmacologyUniversity of Valencia, Valencia, SpainCentro de Investigación Príncipe FelipeValencia, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Andrés-Blasco
authors.affiliation: Institute of Health Research-INCLIVAAvenida Menéndez Pelayo, 4, 46010 Valencia, SpainEndocrinology and Nutrition Department Clinic Hospital and Department of MedicineUniversity of Valencia, Valencia, SpainCIBER de Diabetes y Enfermedades Metabólicas asociadas (CIBERDEM)Valencia, SpainDepartment of FarmacologyUniversity of Valencia, Valencia, SpainCentro de Investigación Príncipe FelipeValencia, Spain.
authors.forename: Andrea
authors.initials: A
authors.lastname: Herrero-Cervera
authors.affiliation: Institute of Health Research-INCLIVAAvenida Menéndez Pelayo, 4, 46010 Valencia, SpainEndocrinology and Nutrition Department Clinic Hospital and Department of MedicineUniversity of Valencia, Valencia, SpainCIBER de Diabetes y Enfermedades Metabólicas asociadas (CIBERDEM)Valencia, SpainDepartment of FarmacologyUniversity of Valencia, Valencia, SpainCentro de Investigación Príncipe FelipeValencia, Spain.
authors.forename: Ángela
authors.initials: Á
authors.lastname: Vinué
authors.affiliation: Institute of Health Research-INCLIVAAvenida Menéndez Pelayo, 4, 46010 Valencia, SpainEndocrinology and Nutrition Department Clinic Hospital and Department of MedicineUniversity of Valencia, Valencia, SpainCIBER de Diabetes y Enfermedades Metabólicas asociadas (CIBERDEM)Valencia, SpainDepartment of FarmacologyUniversity of Valencia, Valencia, SpainCentro de Investigación Príncipe FelipeValencia, Spain Institute of Health Research-INCLIVAAvenida Menéndez Pelayo, 4, 46010 Valencia, SpainEndocrinology and Nutrition Department Clinic Hospital and Department of MedicineUniversity of Valencia, Valencia, SpainCIBER de Diabetes y Enfermedades Metabólicas asociadas (CIBERDEM)Valencia, SpainDepartment of FarmacologyUniversity of Valencia, Valencia, SpainCentro de Investigación Príncipe FelipeValencia, Spain Institute of Health Research-INCLIVAAvenida Menéndez Pelayo, 4, 46010 Valencia, SpainEndocrinology and Nutrition Department Clinic Hospital and Department of MedicineUniversity of Valencia, Valencia, SpainCIBER de Diabetes y Enfermedades Metabólicas asociadas (CIBERDEM)Valencia, SpainDepartment of FarmacologyUniversity of Valencia, Valencia, SpainCentro de Investigación Príncipe FelipeValencia, Spain.
authors.forename: Sergio
authors.initials: S
authors.lastname: Martínez-Hervás
authors.affiliation: Institute of Health Research-INCLIVAAvenida Menéndez Pelayo, 4, 46010 Valencia, SpainEndocrinology and Nutrition Department Clinic Hospital and Department of MedicineUniversity of Valencia, Valencia, SpainCIBER de Diabetes y Enfermedades Metabólicas asociadas (CIBERDEM)Valencia, SpainDepartment of FarmacologyUniversity of Valencia, Valencia, SpainCentro de Investigación Príncipe FelipeValencia, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Piqueras
authors.affiliation: Institute of Health Research-INCLIVAAvenida Menéndez Pelayo, 4, 46010 Valencia, SpainEndocrinology and Nutrition Department Clinic Hospital and Department of MedicineUniversity of Valencia, Valencia, SpainCIBER de Diabetes y Enfermedades Metabólicas asociadas (CIBERDEM)Valencia, SpainDepartment of FarmacologyUniversity of Valencia, Valencia, SpainCentro de Investigación Príncipe FelipeValencia, Spain Institute of Health Research-INCLIVAAvenida Menéndez Pelayo, 4, 46010 Valencia, SpainEndocrinology and Nutrition Department Clinic Hospital and Department of MedicineUniversity of Valencia, Valencia, SpainCIBER de Diabetes y Enfermedades Metabólicas asociadas (CIBERDEM)Valencia, SpainDepartment of FarmacologyUniversity of Valencia, Valencia, SpainCentro de Investigación Príncipe FelipeValencia, Spain.
authors.forename: María Jesús
authors.initials: MJ
authors.lastname: Sanz
authors.affiliation: Institute of Health Research-INCLIVAAvenida Menéndez Pelayo, 4, 46010 Valencia, SpainEndocrinology and Nutrition Department Clinic Hospital and Department of MedicineUniversity of Valencia, Valencia, SpainCIBER de Diabetes y Enfermedades Metabólicas asociadas (CIBERDEM)Valencia, SpainDepartment of FarmacologyUniversity of Valencia, Valencia, SpainCentro de Investigación Príncipe FelipeValencia, Spain Institute of Health Research-INCLIVAAvenida Menéndez Pelayo, 4, 46010 Valencia, SpainEndocrinology and Nutrition Department Clinic Hospital and Department of MedicineUniversity of Valencia, Valencia, SpainCIBER de Diabetes y Enfermedades Metabólicas asociadas (CIBERDEM)Valencia, SpainDepartment of FarmacologyUniversity of Valencia, Valencia, SpainCentro de Investigación Príncipe FelipeValencia, Spain.
authors.forename: Deborah Jane
authors.initials: DJ
authors.lastname: Burks
authors.affiliation: Institute of Health Research-INCLIVAAvenida Menéndez Pelayo, 4, 46010 Valencia, SpainEndocrinology and Nutrition Department Clinic Hospital and Department of MedicineUniversity of Valencia, Valencia, SpainCIBER de Diabetes y Enfermedades Metabólicas asociadas (CIBERDEM)Valencia, SpainDepartment of FarmacologyUniversity of Valencia, Valencia, SpainCentro de Investigación Príncipe FelipeValencia, Spain Institute of Health Research-INCLIVAAvenida Menéndez Pelayo, 4, 46010 Valencia, SpainEndocrinology and Nutrition Department Clinic Hospital and Department of MedicineUniversity of Valencia, Valencia, SpainCIBER de Diabetes y Enfermedades Metabólicas asociadas (CIBERDEM)Valencia, SpainDepartment of FarmacologyUniversity of Valencia, Valencia, SpainCentro de Investigación Príncipe FelipeValencia, Spain gonzaleh@uv.es.
authors.forename: Herminia
authors.initials: H
authors.lastname: González-Navarro
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D018932:Chemokine CCL2 / Q000097:blood; D059305:Diet, High-Fat; D050171:Dyslipidemias / Q000235:genetics / Q000378:metabolism*; D018149:Glucose Intolerance / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D008049:Lipase / Q000235:genetics / Q000378:metabolism*; D050356:Lipid Metabolism / Q000235:genetics*; D008055:Lipids / Q000097:blood; D008099:Liver / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics / Q000378:metabolism*; D010179:Pancreas / Q000378:metabolism
chemical_list: D001786:Blood Glucose; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D007328:Insulin; D008055:Lipids; D008049:Lipase; C495700:Lipc protein, mouse
keywords: glucose intolerance; inflammation; lipase; steatosis