# Novel regulation of insulin action in the liver

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN · 2024 · $306,990

## Abstract

PROJECT SUMMARY
Insulin resistance and type 2 diabetes mellitus (T2DM) have presented an enormous burden to public health and
economy with increasing prevalence. T2DM is characterized by relative insulin deficiency caused by pancreas
β cells dysfunction and insulin resistance in metabolic organs. The liver plays a central role in regulating systemic
glucose and lipid homeostasis. Aberrant hepatic insulin action is believed to be a primary driver of insulin
resistance, in which insulin fails to adequately suppress hepatic glucose production (HGP), while enhances
lipogenesis and triglyceride secretion, a phenomenon referred to as selective insulin resistance. Although
downstream signaling cascades mediating insulin's control of glucose and lipid metabolism have been
extensively studied, the molecular mechanisms underlying the development of insulin resistance and its
differential effect on glucose and lipid metabolism are not well understood. We previously have identified critical
functions of lysophosphatidylcholine acyltransferase 3 (Lpcat3), a phospholipid (PL) remodeling enzyme, in lipid
metabolism in liver. Loss of Lpcat3 selectively reduces polyunsaturated PL in membranes, leading to decreased
membrane fluidity and curvature. Changes in membrane dynamics result in impaired SREBP-1c processing and
lipogenesis, and reduced triglyceride secretion in liver. The overall goal of this proposal is to define the roles of
hepatic Lpcat3 and PL composition in insulin signaling and systemic lipid and glucose metabolism, and their
contribution to the development of insulin resistance. In Aim 1, we will elucidate the mechanisms by which PL
composition regulates insulin sensitivity. In Aim 2, we will investigate whether dysregulation of Lpcat3 expression
mediates selective insulin resistance in T2DM. In Aim 3, we will test the therapeutic potential of targeting Lpcat3
for hyperglycemia and hypertriglyceridemia in T2DM. The results of this work will advance our understanding of
how membrane composition modulates insulin sensitivity and glucose metabolism in liver, and how changes in
membrane biophysical properties contribute to the pathogenesis of insulin resistance.

## Key facts

- **NIH application ID:** 10766683
- **Project number:** 5R01DK128167-03
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
- **Principal Investigator:** Bo Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $306,990
- **Award type:** 5
- **Project period:** 2022-02-01 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10766683

## Citation

> US National Institutes of Health, RePORTER application 10766683, Novel regulation of insulin action in the liver (5R01DK128167-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10766683. Licensed CC0.

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