Abstract 556: Deficiency of Probhitin-1 in Hepatocytes Alters Systemic Glucose Regulation

Abstract

Prohibitins 1 and 2 (PHB1 and PHB2) are lipid raft proteins that form a hetero-oligomeric complex known to localize to the cytoplasmic, nuclear, and mitochondrial membranes. These complexes play important roles in pro-survival and metabolic decisions including inflammation. PHB1 is important for mitochondria biogenesis and function and is excreted into the serum. Mice challenged with an intraperitoneal injection of lipopolysaccharide (LPS), a treatment that normally results in decreased cardiac function, show increased serum PHB. Injection of recombinant PHB1 (rPHB1) following LPS injection can rescue cardiac function. Work in our lab with cultured cardiomyocytes and multiple rodent models of severe sepsis supports the hypothesis that PHB1 is a liver-derived acute phase protein. To test this hypothesis, we utilized AAV- Cre recombinase infection driven by human thyroid hormone-binding globulin (TBG), a liver specific promotor (AAV8-TBG-iCre), on our PHB1 floxed mice (PHB1 fl/fl ). This liver specific knockdown of PHB1 allowed us to look at PHB1 levels in the serum of unstressed PHB1 fl/fl mice. We discovered a loss of PHB1 in the liver tissue of floxed mice and significantly lower serum levels of PHB was found in homozygotes compared to wild types. Additionally, mice with liver specific loss of PHB1 show metabolic changes including significant weight loss three weeks following injection and changes to body composition and a trend of decreases in brown fat and inguinal fat mass. In addition to these body changes, we found that liver specific loss resulted in sexual dimorphism in insulin sensitivity. Homozygous males showed a significant difference in their ability to clear glucose following a glucose challenge in a glucose tolerance test. However, following an insulin tolerance test, female homozygotes showed increased insulin sensitivity where males did not. Both males and females show a trend towards attenuated gluconeogenesis following a pyruvate tolerance test. Overall, we have begun to characterize novel findings to the metabolic state of mice lacking PHB1 only in the liver. Our aim is to further explore if these differences are due to the changes in liver PHB1 or due to changes in circulating serum PHB1.