# Role of Beta Spectrin and Smad in Alcohol-Induced Liver and GI Cell Proliferation

> **NIH NIH R01** · FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH · 2024 · $443,383

## Abstract

PROJECT SUMMARY
Alcohol-related liver disease (ALD) and nonalcoholic steatohepatitis (NASH) are two reasons Americans mostly
require a liver transplant. Furthermore, aldehyde dehydrogenase gene 2 (ALDH2) deficiency, which impairs
alcohol and lipid metabolism, affects ~560 million people globally.
Our earlier studies show that a pathway from TGF-β to βII-spectrin (encodes the disordered protein βII-spectrin)
via SMAD3 (a TGF-β -activated transcription factor) is essential for proper development of the liver and
preventing many liver pathologies. βII-spectrin-deficient mice are highly susceptible to alcohol-induced liver
injury, and complete knockout of this gene results in embryonic death with features like fetal alcohol syndrome.
Compromised TGF-β signaling through SMAD3 and βII-spectrin dysregulates ALDH1A and ALDH2 genes and
disrupts DNA repair, contributing to oncogenesis from elongated telomeres and genome instability.
To explore the roles of βII-spectrin and the TGF-β pathway in aldehyde-related and alcohol-related liver injury,
we generated Aldh2-/-Sptbn1+/- (ASKO) double-knockout mice, which become obese and develop NASH and
characteristics of metabolic syndrome (MetS). Their livers have altered lipid profiles, increased reactive
aldehydes, and increased lipid synthesis. Treating Aldh2-/- mice with siRNA targeting βII-spectrin reduces diet-
induced lipid accumulation and improves glucose handling. We hypothesize that hepatocyte stress from high
lipid levels, reactive aldehydes, such as 4-hydroxynonenol (4-HNE), or inflammation activates caspases that
cleave βII-spectrin, which, in turn, promote lipid synthesis by interacting with SREBP1 (sterol regulatory element
binding protein1). This process also diverts βII-spectrin from TGF-β-SMAD3 signaling, activating fibrogenic and
oncogenic pathways instead. We will explore how cleavage of βII-spectrin and aldehyde-modification of βII-
spectrin affect the interactions between βII-spectrin, SMAD3, and SREBP1 by addressing the following specific
aims:
Aim 1. Determine the hepatocyte-specific roles of βII-spectrin by studying Aldh2-/- mice crossed with liver-specific
Sptbn1 knockout mice.
Aim 2. Define molecular mechanisms by which the interaction between βII-spectrin and SREBP1 promotes
lipogenesis.
Aim 3. Assess the translational relevance of SPTBN1 and ALDH2 in human obesity and NASH, and if
pathological effects are reduced by siRNA targeting βII-spectrin.
The outlined studies are aimed at improving the understanding of diet-induced fatty liver disease in the context
of ALDH2 deficiency. The outcomes promise to expose the many intricacies of liver diseases and inform the
development of novel intervention strategies for liver-associated diseases, such as MetS, ALD, NAFLD, and
NASH.

## Key facts

- **NIH application ID:** 10801085
- **Project number:** 2R01AA023146-18A1
- **Recipient organization:** FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
- **Principal Investigator:** Lopa Mishra
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $443,383
- **Award type:** 2
- **Project period:** 2024-08-20 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10801085

## Citation

> US National Institutes of Health, RePORTER application 10801085, Role of Beta Spectrin and Smad in Alcohol-Induced Liver and GI Cell Proliferation (2R01AA023146-18A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10801085. Licensed CC0.

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