Impact of the estrogen receptor alpha on Non-Alcoholic Fatty Liver Disease and energetic metabolism of the liver

• Grant number: 18/04956-5
• Support Opportunities: Research Grants - Young Investigators Grants
• Start date: July 01, 2019
• End date: June 30, 2024
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: João Paulo Gabriel Camporez
• Grantee: João Paulo Gabriel Camporez
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated researchers: Jose Donato Junior ; Silvana Auxiliadora Bordin da Silva
• Associated scholarship(s): 20/09094-1 - Impact of galectin-3 inhibition on hepatic insulin resistance and energy metabolism in Non-Alcoholic Steato-Hepatitis, BP.PD; 20/16160-0 - Progesterone effects on energy metabolism and insulin resistance in menopause, BP.MS; 21/02638-9 - Impact of estrogen receptor alpha on non-alcoholic fatty liver disease and liver energy metabolism, BP.MS; 21/03406-4 - Effect of reduced expression by adeno-associated virus of the estrogen receptor alpha on hepatic metabolism, BP.MS; 19/18965-9 - Effect of increased estrogen receptor alpha expression by adeno-associated virus on hepatic metabolism, BP.IC

Abstract

Lifestyle and increased consumption of high fat diets contribute greatly to the development of Obesity, insulin resistance, Type 2 Diabetes (DM2), and cardiovascular diseases. In addition, cardiovascular diseases associated with metabolic complications, such as insulin resistance and Obesity, are less prevalent in young women than in men of the same age or postmenopausal women. Several mechanisms are essential as causes of insulin resistance, such as abnormal lipid metabolism and its ectopic accumulation, mitochondrial dysfunction, inflammation, and endoplasmic reticulum stress. One of the consequences of the Western lifestyle and high fat diet is Non Alcoholic Fatty Liver Disease (NAFLD), which affects about 30% of adults and up to 10% of children in developed countries. In the last decades, data from clinical and experimental studies have revealed that estradiol (more potent estrogen) contributes greatly to glycemic homeostasis. In fact, a reduction in the concentration of estrogen during a menopause is associated with increased visceral fat and, in turn, metabolic diseases like insulin resistance, DM2, and cardiovascular diseases. Since the liver is a central organ in the development of DM2, the general aim of this project is to study (in vivo and in vitro) Estrogen Receptor alpha (ER±) on liver energetic metabolism using primary cellular culture of hepatocytes and animals with modulation of ER± expression in the liver (knockdown or overexpression) through the use of Adeno-Associated Virus (AAV) for evaluation. This project allows the establishment of a new line of research in the department involving the impact of the signaling of sex hormones, such as estradiol, on energy metabolism, in addition to the mechanisms involved in the development of NAFLD and possible targets and new approaches to the treatment/prevention of NAFLD and DM2. In addition, this project allows the establishment of a "gold standard" technique of hyperinsulinemic-normoglycemic clamp in mice with the use of radioactive tracers to determine possible alterations on glucose metabolism in vivo. The establishment of this technique in the department will contribute with excellence to the high demand for phenotyping of mice regarding glucose metabolism. (AU)

Scientific publications

(9)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

JIANG, ZEWEN; ZHAO, MENG; VOILQUIN, LAETITIA; JUNG, YUNSHIN; AIKIO, MARI A.; SAHAI, TANUSHI; DOU, FLORENCE Y.; ROCHE, ALEXANDER M.; CARCAMO-ORIVE, IVAN; KNOWLES, JOSHUA W.; et al. Isthmin-1 is an adipokine that promotes glucose uptake and improves glucose tolerance and steatosis. Cell Metabolism, v. 33, n. 9, p. 1836+, SEP 7 2021. (18/04956-5)

HAN, MYOUNG SOOK; PERRY, RACHEL J.; CAMPOREZ, JOAO-PAULO; SCHERER, PHILIPP E.; SHULMAN, GERALD I.; GAO, GUANGPING; DAVIS, ROGER J.. A feed-forward regulatory loop in adipose tissue promotes signaling by the hepatokine FGF21. GENES & DEVELOPMENT, v. 35, n. 1-2, p. 133-146, JAN 1 2021. (18/04956-5)

CAMARGO, FELIPE N.; MATOS, SANDRO L.; ARAUJO, LAYANNE C. C.; CARVALHO, CARLA R. O.; AMARAL, ANDRESSA G.; CAMPOREZ, JOAO PAULO. Western Diet-Fed ApoE Knockout Male Mice as an Experimental Model of Non-Alcoholic Steatohepatitis. CURRENT ISSUES IN MOLECULAR BIOLOGY, v. 44, n. 10, p. 12-pg., 2022-10-01. (18/04956-5, 19/18965-9, 20/09094-1)

WASINSKI, FREDERICK; CHAVES, FERNANDA M.; PEDROSO, JOAO A. B.; MANSANO, NAIRA S.; CAMPOREZ, JOAO PAULO; GUSMAO, DANIELA O.; LIST, EDWARD O.; KOPCHICK, JOHN J.; FRAZAO, RENATA; SZAWKA, RAPHAEL E.; et al. Growth hormone receptor in dopaminergic neurones regulates stress-induced prolactin release in male mice. Journal of Neuroendocrinology, v. 33, n. 3, MAR 2021. (18/04956-5, 17/02983-2, 20/01318-8, 17/21840-8, 16/20897-3, 17/21854-9, 17/22189-9)

MOREIRA, GABRIELA V.; MATOS, SANDRO L.; CAMARGO, FELIPE N.; ARAUJO, LAYANNE; MURATA, GILSON M.; CARVALHO, CARLA R. O.; CAMPOREZ, JOAO PAULO. Estradiol Protects Female ApoE KO Mice against Nonalcoholic Steatohepatitis. Diabetes, v. 69, p. 2-pg., 2020-06-01. (18/04956-5)

ARAUJO, LAYANNE C. C.; CRUZ, ALESSANDRA G.; CAMARGO, FELIPE N.; SUCUPIRA, FELIPE G.; MOREIRA, GABRIELA V.; MATOS, SANDRO L.; AMARAL, ANDRESSA G.; MURATA, GILSON MASAHIRO; CARVALHO, CARLA R. O.; CAMPOREZ, JOAO PAULO. Estradiol Protects Female ApoE KO Mice against Western-Diet-Induced Non-Alcoholic Steatohepatitis. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 24, n. 12, p. 15-pg., 2023-06-01. (19/18965-9, 18/04956-5, 20/09094-1, 21/02638-9)

TALARICO, CARLOS H. Z.; ALVES, ESTER S.; DOS SANTOS, JESSICA D. M.; SUCUPIRA, FELIPE G. S.; ARAUJO, LAYANNE C. C.; CAMPOREZ, JOAO PAULO. Progesterone Has No Impact on the Beneficial Effects of Estradiol Treatment in High-Fat-Fed Ovariectomized Mice. CURRENT ISSUES IN MOLECULAR BIOLOGY, v. 45, n. 5, p. 12-pg., 2023-05-03. (18/04956-5, 20/09094-1, 20/16160-0, 21/02638-9)

PEDROSO, JOAO A. B.; CAMPOREZ, JOAO PAULO; BELPIEDE, LUCIANA T.; PINTO, RAFAELA S.; CIPOLLA-NETO, JOSE; DONATO, JOSE. Evaluation of Hepatic Steatosis in Rodents by Time-Domain Nuclear Magnetic Resonance. DIAGNOSTICS, v. 9, n. 4, DEC 2019. (14/50457-0, 18/04956-5, 17/02983-2)

HABTEMICHAEL, ESTIFANOS N.; LI, DON T.; CAMPOREZ, JOAO PAULO; WESTERGAARD, XAVIER O.; SALES, I, CHLOE; LIU, XINRAN; LOPEZ-GIRALDEZ, FRANCESC; DEVRIES, STEPHEN G.; LI, HANBING; RUIZ, DIANA M.; et al. Insulin-stimulated endoproteolytic TUG cleavage links energy expenditure with glucose uptake. NATURE METABOLISM, v. 3, n. 3, MAR 2021. (18/04956-5)