Biology subjects

DiPietro, L.

Publications and source records attributed to DiPietro, L..

2 recordsLinked to original sources

bioRxiv2024

Increased Postprandial Metabolic Flexibility is Associated with Higher Body Fat Percentages in Healthy Young Adults

PURPOSEBecause higher adiposity is associated with cardiometabolic disease, we assessed the relationship between body composition (body fat percentage; BF%) and postprandial metabolic flexibility. METHODSYoung adults (n = 27, n = 15 females, BMI = 27.1 {+/-} 4.5; BF% = 30.4 {+/-} 8.7) without overt pathology completed a 100g oral glucose tolerance test (OGTT). Indirect calorimetry before (fasting) and following (30, 60, 90, 120 min) consumption was used to calculate respiratory exchange ratio (RER) and oxidation of carbohydrates (CHO) and fats (FOX). Serum and plasma were collected at corresponding time points and analyzed for blood glucose, insulin, and NEFAs. Data from individuals with normal weight were compared to those with overweight/obesity by two-way repeated measures ANVOA. The effect of BF% on postprandial metabolism was tested via linear mixed models while adjusting for potential confounders. RESULTSDuring the OGTT, blood glucose, serum insulin, plasma lactate, RER, and CHO all significantly increased while plasma NEFAs and whole-body FOX decreased (all p<0.05). BF% modified the relationship between postprandial RER and time (p = 0.019) as well as postprandial CHO and time (p = 0.023) without an effect of BF% on FOX; individuals with higher BF% increase their RER and CHO faster and to a greater extent than those with lower BF%. CONCLUSIONBody fat percentage is associated with greater postprandial metabolic flexibility during an OGTT in young adults. Despite increased adiposity, metabolic flexibility may be preserved, representing a compensatory adaptation to decreased glucose storage in the postprandial period.

physiology↗

bioRxiv2022

Evaluation of PRKACA as a Therapeutic Target for Fibrolamellar Carcinoma

Background & AimsFibrolamellar carcinoma (FLC) is a rare, difficult-to-treat liver cancer primarily affecting pediatric and adolescent patients, and for which precision medicine approaches have historically not been possible. The DNAJB1-PRKACA gene fusion was identified as a driver of FLC pathogenesis. We aimed to assess whether FLC tumors maintain dependency on this gene fusion and determine if PRKACA is a viable therapeutic target. MethodsFLC patient-derived xenograft (PDX) shRNA cell lines were implanted subcutaneously into female NOD-SCID mice and tumors were allowed to develop prior to randomization to doxycycline (to induce knockdown) or control groups. Tumor development was assessed every 2 days. To assess the effect of treatment with novel selective PRKACA small molecule kinase inhibitors, BLU0588 and BLU2864, FLC PDX tumor cells were implanted subcutaneously into NOD-SCID mice and tumors allowed to develop. Mice were randomized to treatment (BLU0588 and BLU2864, orally, once daily) or control groups and tumor size determined as above. ResultsKnockdown of DNAJB1-PRKACA reversed a FLC-specific gene signature and reduced PDX tumor growth in mice compared to the control group. Furthermore, FLC PDX tumor growth was significantly reduced with BLU0588 and BLU2864 treatment versus control (P = 0.003 and P = 0.0005, respectively). ConclusionsWe demonstrated, using an inducible knockdown and small molecule approaches, that FLC PDX tumors were dependent upon DNAJB1-PRKACA fusion activity. In addition, this study serves as a proof-of-concept that PRKACA is a viable therapeutic target for FLC and warrants further investigation.

cancer biology↗