# The mTOR-ETV5 signaling in gastric X/A like cells and its role in hepatic lipid metabolism and steatosis

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $600,297

## Abstract

Our preliminary studies have identified a novel stomach-liver humoral axis. Mechanistic target of rapamycin (mTOR) signaling pathway in the gastric X/A like cells coordinates nutrient availability with the hepatic lipid metabolism via ghrelin. Our studies have also identified ETV5, an ETS-related transcriptional factor, as the novel downstream target of mTOR signaling. Further, ETV5 alters the expression of ghrelin O-acyltransferase and subsequent acylation of ghrelin. Although X/A like cells in the stomach produce and secrete both acyl- and desacyl-ghrelin, only acyl-ghrelin binds and activates its receptor: growth hormone secretagogue receptor 1a (GHSR1a). Acyl-ghrelin was originally demonstrated to act via the hypothalamus to stimulate food intake. Our data now indicate that acyl-ghrelin regulates hepatic lipid synthesis via its direct action on hepatocytes. We thus propose four aims to investigate the functions of gastric mTOR-ETV5 signaling pathway in the production and secretion of acyl-ghrelin and its effects on hepatic lipid metabolism. Aim 1 will establish ETV5 as the downstream target of mTOR, mediating its unique regulation of ghrelin acylation in X/A like cells. Aim 2, using transgenic mice in which mTOR signaling in gastric X/A like cells is either activated or suppressed, will demonstrate that gastric mTOR signaling affects hepatic lipid metabolism and the development of hepatic steatosis induced by a high-fat diet. Aim 3 will examine whether ETV5 in gastric X/A like cells alters hepatic lipid metabolism and the development of hepatic steatosis induced by a high-fat diet, using mice in which ETV5 gene expression in gastric X/A like cells is altered. Aim 4 will determine whether acyl-ghrelin mediates the effects of gastric mTOR on hepatic lipid metabolism via its activation of GHSR1a on hepatocytes, Kupffer cells and/or hypothalamic (HTH) neurons. We will use cell biological and transgenic techniques to achieve these goals. Completion of this proposal will advance a completely new therapeutic approach for NAFLD, one directed at gastric sites.

## Key facts

- **NIH application ID:** 10274428
- **Project number:** 1R01DK129360-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Weizhen Zhang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $600,297
- **Award type:** 1
- **Project period:** 2021-07-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10274428

## Citation

> US National Institutes of Health, RePORTER application 10274428, The mTOR-ETV5 signaling in gastric X/A like cells and its role in hepatic lipid metabolism and steatosis (1R01DK129360-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10274428. Licensed CC0.

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