# Acot9 Promotes Lipotoxicity

> **NIH NIH R03** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $84,750

## Abstract

Project Summary/Abstract
Obesity-induced lipotoxicity is the primary pathophysiological defect that predisposes to type 2 diabetes and
non-alcoholic fatty liver disease (NAFLD). Because current management options remain limited, identification
of new regulatory mechanisms that govern the maladaptive metabolic response to excess lipids should serve
to identify novel opportunities for pharmacologic intervention. The long-term objective of this research is to
define a novel molecular mechanism by which excess fatty acids impair lipid and glucose homeostasis. The
rationale is that the identification of a novel mechanism that promotes lipotoxicity could lead to new therapeutic
targets. Our preliminary studies indicate that acyl-CoA thioesterase 9 (Acot9), an enzyme that deactivates fatty
acids in vitro, promotes adiposity and hepatic glucose production (HGP) in mice in the setting of excess lipid
uptake. Guided by extensive preliminary data, the central hypothesis of this research plan is that, in response
to overnutrition, Acot9-mediated regulation of lipid metabolism impairs hepatic insulin signaling and
exacerbates HGP. This will be tested in two specific aims: 1) Identify the molecular mechanisms by which
Acot9 regulates hepatic lipid and glucose metabolism; 2) Determine the molecular mechanisms by which high
fat diet regulates the subcellular localization and the thioesterase activity of Acot9. In aim 1, the effect of Acot9
expression on glucose homeostasis will be determined in mice with systemic and liver-specific ablation of
Acot9 by hyperinsulinemic/euglycemic clamp. Liver histology, mass spectrometry of lipidomics and established
assays to measure lipid levels will be used to characterize the effect of Acot9 on lipid metabolism. VLDL
secretion will be assessed following Tyloxapol injection. β-oxidation will be determined using radiolabeled
palmitate and Seahorse flux analyzer. Fatty acid uptake, efflux, lipogenesis and lipolysis will be studied in
primary adipocytes using radiolabeled palmitate or acetate. Immunoblot and qPCR analyses will measure
established regulators of insulin signaling, HGP and lipid homeostasis. It is anticipated that Acot9 will promote
insulin resistance and HGP by exacerbating the formation of lipotoxic intermediates such as reactive oxygen
species, ceramides and diacylglycerol and by increasing β-oxidation. Aim2 will test whether high fat diet-
induced expression and phosphorylation of Acot9 alters the subcellular localization, substrate specificity and
activity of Acot9. This will be tested in palmitate-treated cells using microscopy and in thioesterase activity
assays using recombinant Acot9. We expect that excessive nutrition will increase localization of Acot9 to ER
and its affinity for saturated fatty acyl-CoA. Overall, this proposal will elucidate mechanisms by which Acot9
promotes lipotoxicity, which is significant because trafficking of fatty acids varies in health and disease. These
studies are expected to ...

## Key facts

- **NIH application ID:** 9857595
- **Project number:** 5R03DK117247-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Baran Ersoy
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $84,750
- **Award type:** 5
- **Project period:** 2019-02-01 → 2021-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9857595

## Citation

> US National Institutes of Health, RePORTER application 9857595, Acot9 Promotes Lipotoxicity (5R03DK117247-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9857595. Licensed CC0.

---

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