# Hepatic Energy Fluxes, NASH, and Vertical Sleeve Gastrectomy

> **NIH NIH R21** · UNIVERSITY OF MINNESOTA · 2020 · $192,500

## Abstract

Twenty-five percent of the United States population has nonalcoholic fatty liver disease (NAFLD), a disease that
includes hepatic fatty infiltration alone (simple steatosis) or steatosis plus inflammation, liver cell injury and death
[nonalcoholic steatohepatitis (NASH), which develops in 25% of patients with NAFLD]. NAFLD spectrum
disorders are the hepatic manifestation of obesity, insulin resistance, and type 2 diabetes. NASH leads to liver
fibrosis, an elevated risk of cirrhosis and hepatocellular carcinoma, and will soon be the leading cause of liver
transplantation in the U.S. In the U.S., the cost of management of NASH and its complications is $32 billion
annually. Durable therapies are lacking for the NASH spectrum and an acceptable pharmaceutical intervention
is not approved. The vertical sleeve gastrectomy(VSG) is a bariatric surgical procedure that dramatically reduces
liver injury and favors NASH remission. Importantly, not all patients with NASH demonstrate histologic
improvements (as assessedby NAFLD activity score, NAS) following bariatric surgery, and in a small percentage
of patients the disease may progress. Furthermore, there are no known antecedent biomarkers that predict
histologic changes of NAFLD/NASH following bariatric surgery. In these proposed studies, formal quantifications
of liver oxidative and gluconeogenic fluxes (‘hepatic energy fluxes’) will be performed at baseline in obese
patients who have all received preoperative liver biopsies for histopathological determination, liver MRI-derived
proton density fat fraction and elastography assessment of fibrosis, and intravenous glucose tolerance tests, all
prior to VSG. The interdisciplinary team will then determine how these preoperative metabolic flux indices
correlate with pre- and postoperative histopathological, radiographic, and clinical indices. Thus, the premise of
this study is that deranged hepatic mitochondrial metabolism is a key biomarker and mediator of the
NAFLD/NASH continuum, and the central hypothesis to be tested is that preoperative hepatic fat oxidation and
glucose production flux parameters differ between NAFLD versus NASH (diminished in NASH), and response
of the liver to bariatric surgery can be predicted by preoperative fluxes. In Aim 1, hepatic metabolic fluxes will be
quantified in humans with non-NASH NAFLD (NAS <3) versus NASH (NAS ≥ 4 with at least a score of ‘1’ for
ballooning degeneration), testing the hypothesis that hepatic energy fluxes are decreased in human NASH
compared to uncomplicated NAFLD. A secondary hypothesis is that oxidative fluxes do not directly correlate with
any specific index component of NAS. In Aim 2, post-VSG histopathological, radiographic, and clinical outcomes
will be compared to preoperative hepatic energy fluxes, testing the hypothesis that preoperative hepatic energy
fluxes will predict these outcomes similarly to standard histopathological, radiographic, and metabolic
parameters. These proof-of-concept datasets...

## Key facts

- **NIH application ID:** 9985838
- **Project number:** 5R21DK122832-02
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Peter A Crawford
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $192,500
- **Award type:** 5
- **Project period:** 2019-08-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9985838

## Citation

> US National Institutes of Health, RePORTER application 9985838, Hepatic Energy Fluxes, NASH, and Vertical Sleeve Gastrectomy (5R21DK122832-02). Retrieved via AI Analytics 2026-06-14 from https://api.ai-analytics.org/grant/nih/9985838. Licensed CC0.

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