# Role of the Cell Adhesome in Obesity-related Liver Diseases

> **NIH NIH R01** · VANDERBILT UNIVERSITY · 2021 · $506,338

## Abstract

PROJECT SUMMARY:
 A consequence of modernization is that people have adopted diets for which they are
poorly adapted and live inactive lifestyles. This has resulted in dramatic increases in obesity,
dyslipidemias, Type 2 diabetes, as well as other aggregates of the Metabolic Syndrome.
Metabolic dysregulation of the liver is an early and prominent defect in the sequalae that lead to
these conditions. A primary defect evident in the liver is a selective insulin resistance
characterized by an impairment in insulin suppression of endogenous glucose production
(EGP), but intact lipogenesis and lipid storage. This creates impaired regulation of blood
glucose and an unhealthy accumulation of fat in the liver. Liver fibrosis is closely correlated to
insulin resistance. We have compelling evidence that the cell “adhesome” couples changes in
liver extracellular matrix to insulin resistance. The adhesome consists of integrin αβ
heterodimers that transmit extracellular signals to protein complexes necessary for cells to
adapt to their environment. We found that disruption of the adhesome either by disrupting the
integrin α1 subunit or by deletion of the integrin-linked kinase (ILK) in the cell prevents fatty liver
in obese mice. Interestingly, only ILK deletion prevents resistance to insulin suppression of GP.
The proposed studies will define how the cell adhesome is coupled to hepatic metabolic
regulation. Studies will use genetic mouse models to test the hypotheses that i) deleterious
effects of ILK in the liver of diet-induced obese mice require that it complex with binding
partners, PINCH and parvin; ii) ILK deletion reverses pre-existing fatty liver and IR in diet-
induced obese mice; and iii) ILK requires Itgβ1 for its metabolic effects in DIO mice. These
hypotheses will be addressed using isotopic methods to measure fatty acid synthesis and liver
fatty acid uptake, triglyceride formation and export, and glucose fluxes in catheterized,
conscious genetic mouse models. Hepatocytes will be isolated from these mouse models to
define mechanisms that are particularly complex in the whole organism. Biochemical and
histological analyses will identify pathways and regulatory mechanisms involved in metabolic
regulation of nutrient fluxes by the cell adhesome of lean and diet-induced obese mice.
Functional tests of the endoplasmic reticulum and mitochondria will define the role of these
systems essential to fatty acid synthesis and nutrient oxidation, respectively. These studies will
define the role of the cell adhesome in obesity-related liver metabolic disease and it will identify
potential targets for treating the metabolic effects of obesity on the liver.

## Key facts

- **NIH application ID:** 10220947
- **Project number:** 5R01DK050277-25
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** DAVID H WASSERMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $506,338
- **Award type:** 5
- **Project period:** 1995-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10220947

## Citation

> US National Institutes of Health, RePORTER application 10220947, Role of the Cell Adhesome in Obesity-related Liver Diseases (5R01DK050277-25). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10220947. Licensed CC0.

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