THE PAN TGF-B INHIBITOR BRECEPT ENCODED BY A LENTIVIRAL VECTOR AMELIORATES METABOLIC SYNDROME IN A MURINE MODEL

CÁMARA, CAROLINA ANAHÍ; LA COLLA, ANABELA; RODRÍGUEZ, TANIA MELINA; ECHARTE, STELLA MARIS; DEWEY RICARDO ALFREDO; CHISARI, ANDREA NANCY

Mar del Plata

Congreso; Reunión Conjunta SAIC SAI FAIC SAFIS 2022; 2022

SAIC-SAI-SAFIS

Metabolic syndrome (MS) is a growing public health problem closelyrelated to insulin resistance (IR) and obesity and is also associatedwith an increased risk of developing non-alcoholic fatty liverdisease, cardiovascular diseases, and type II diabetes. Nowadays,treatments for MS patients are limited. Molecular signals betweenthe liver and adipose tissue could regulate lipid storage in adiposetissue. The TGF-β pathway is linked to hepatic steatosis and liverfibrosis. Brecept (Br), a pan TGF-β inhibitor, was developed by fusingTβRII-SE, a novel soluble TGF-β type II receptor splice variant,to the Fc portion of human IgG (TβRII-SE/Fc). We aimed to studythe effect of lentiviral-mediated liver overexpression of Br (Lv-Br) in a rat model of MS induced by Western Diet (WD). We comparedthree groups: control diet, WD, and WD+Lv-Br that received an intrahepaticinjection of the lentiviral vector encoding Br at week 10.At week 18, we observed lower glycemia (p<0.05) and IR (p<0.01)in the Lv-Br group than in the WD group by insulin tolerance test. Inweek 21, animals were sacrificed. In liver tissue stained with H&Eand Masson’s Trichome, we observed in the WD+Lv-Br group, comparedwith the WD group, a remarkably decreased microvesicularsteatosis and inflammatory infiltrate in the portal triad (PT). Furthermore,we found that fibrosis in the central vein (CV) and PT wassignificantly reduced (p<0.001). In adipose tissue stained with H&E,we observed hyperplasia (p<0.01) and a tendency to atrophy in adipocytes,comparing the WD+Lv-Br group with the WD group. Finally,in transmission electron microscopy liver sections, we observed animportant decrease in lipid droplet number/field (p<0.001), mean lipiddroplet area/field (p<0.001), endoplasmic reticulum hypertrophy,and lower swollen mitochondria in the WD+Lv-Br group than in theWD group. Therefore, these results suggest that liver overexpressionof Br exerts a beneficial effect against MS induced by a WDin rats.