# Pathophysiologic mechanisms leading to intrahepatic fat accumulation in obese youth

> **NIH NIH R01** · YALE UNIVERSITY · 2021 · $668,756

## Abstract

Project Summary
Nonalcoholic fatty liver disease (NAFLD) is the most common hepatic disease in pediatrics, affecting about
30% of obese youth. The term NAFLD defines a wide spectrum of disease severity ranging from simple
intrahepatic fat accumulation without liver injury (steatosis) to nonalcoholic steatohepatitis (NASH), fibrosis and
cirrhosis. A 20-year retrospective study has shown that subjects who develop NAFLD during their youth have
about 13 times higher mortality rate for end-stage liver disease than healthy subjects of similar age and gender
NAFLD is highly prevalent among Hispanic youth, while non-Hispanic Black (NHB) youth are protected against
intrahepatic fat accumulation even in the presence of severe obesity and insulin resistance. Understanding the
pathophysiology underlying these differences could shed new light on the mechanisms leading to NAFLD in
obese youth. Our preliminary data suggest that Hispanic and NHB obese youth might have a different ability to
metabolize carbohydrates (CHO) through glycolysis, with Hispanics showing higher glycolysis than NHB.
Therefore, Hispanics might experience a higher rated tricyclic acid cycle (TCA) and hepatic de novo
lipogenesis (DNL). In the present study we aim to address the following questions 1) Is the different
susceptibility between Hispanics and NHB in developing NAFLD due to a higher capability of Hispanics to
metabolize CHO through glycolysis, TCA cycle and DNL? 2) Do these metabolic changes anticipate the onset
of the disease in Hispanic youth? 3) Are the higher rates of glycolysis, TCA and DNL driven by high but not-
pathologic changes in glucose levels over time? To address our aims we plan to recruit 30 Hispanics and 30
NHB obese youth and to measure glycolysis by using a new method to assess lactate kinetics and to
determine the TCA cycle and DNL by using 13C-Propionate and D2O. Moreover, we will assess glycolysis
and intrahepatic fat content in a group of 150 Hispanic obese youth without fatty liver at baseline every 12
months for two years to determine whether higher glycolytic rates precede intrahepatic fat accumulation. To
assess whether metabolic changes in glycolysis are driven by higher but not-pathologic glucose levels, we will
measure glucose changes over ten days every six months by using a continuous glucose monitoring system. If
successful these studies will provide novel insight into the pathogenesis of pediatric NAFLD and will open new
avenues to test novel therapeutic approaches.

## Key facts

- **NIH application ID:** 10153179
- **Project number:** 1R01MD015974-01
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Nicola Santoro
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $668,756
- **Award type:** 1
- **Project period:** 2021-04-21 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10153179

## Citation

> US National Institutes of Health, RePORTER application 10153179, Pathophysiologic mechanisms leading to intrahepatic fat accumulation in obese youth (1R01MD015974-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10153179. Licensed CC0.

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