# Role of Fbxo48-mediated AMPK proteostasis in the pathogenesis and treatment of NAFLD

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $414,914

## Abstract

Project summary/Abstract
The number of overweight and obese individuals in the U.S. has increased dramatically over the last two decades. With
this rise, the prevalence of a number of obesity-associated metabolic diseases, such as type 2 diabetes (T2D) and non-
alcoholic fatty liver disease (NAFLD), has similarly sky rocketed. NAFLD encompasses a range of hepatocellular
alterations, including simple steatosis and steatosis with inflammation (NASH), which can lead to fibrosis, cirrhosis and
hepatocellular carcinoma. Hepatic insulin resistance, changes in mitochondrial metabolism, inflammatory signaling,
extracellular vesicle signaling and/or altered intestinal microbial diversity are all proposed to contribute the pathogenesis
of NAFLD and NASH. However, the mechanistic basis for the pathogenesis of NAFLD remains incompletely understood
and there are currently no approved treatments for NAFLD. 5'-AMP-activated protein kinase (AMPK) is a cellular energy
sensor that coordinates metabolic pathways to balance energy demand with production, and growing evidence suggests
that loss of AMPK activity and its downstream signaling pathways contributes to NAFLD. This proposal will test the
hypothesis that increased phosphorylation-dependent, ubiquitin/proteasomal-mediated degradation of AMPK contributes
to the pathogenesis of obesity-associated NAFLD. They will further establish the identity of the F-box protein that
mediates the specific recognition of phosphorylated AMPK by the Skp-Cullin1-Rbx1 E3 ligase complex. Finally, studies
herein will address how modulating the expression or activity of the putative F-box protein during the pathogenesis of
NAFLD or after development of established NASH impacts major outcomes associated with these diseases. These goals
will be achieved through a combination of approaches including cell biology, amino acid and peptide chemistry, animal
physiology, metabolic isotope tracing, and homology modeling- and molecular docking-based drug design and
optimization. This approach will leverage the unique and complimentary expertise of the participating investigators of this
multi-principal investigator proposal, leading to new knowledge regarding the pathogenesis and a potential treatment of
NAFLD.

## Key facts

- **NIH application ID:** 10075929
- **Project number:** 5R01DK119627-03
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Michael J. Jurczak
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $414,914
- **Award type:** 5
- **Project period:** 2019-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10075929

## Citation

> US National Institutes of Health, RePORTER application 10075929, Role of Fbxo48-mediated AMPK proteostasis in the pathogenesis and treatment of NAFLD (5R01DK119627-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10075929. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*