Document text
Principal Investigator: Lopa Mishra
Organization: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
Fiscal Year: 2024
Award: $443,383
Funding agency: National Institute on Alcohol Abuse and Alcoholism
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.
Terms: <(TNF)-α><3-D><3-Dimensional><3D><ALDH><Acetaldehyde><Acetic Acids><Address><Affect><Alcohol Chemical Class><Alcoholic Liver Diseases><Alcohols><Aldehydes><Alimentary Canal><American><Apopain><Apoptosis-Related Cysteine Protease Caspase 3><Basal Transcription Factor><Basal transcription factor genes><Binding><Body Tissues><Bone-Derived Transforming Growth Factor><CASP-3><CASP3><CASP3 gene><CPP-32><CPP32><CPP32 protein><CPP32B><CPP32beta><Cachectin><Caspase><Caspase Gene><Cell Body><Cell Communication and Signaling><Cell Growth in Number><Cell Line><Cell Multiplication><Cell Proliferation><Cell Signaling><Cell-Death Protease><CellLine><Cells><Cellular Proliferation><Characteristics><Clinical><Complex><Cysteine Endopeptidases><Cysteine Protease><Cysteine Protease CPP32><Cysteine Protease CPP32 Gene><Cysteine Proteinases><D-Glucose><DNA Damage Repair><DNA Repair><Data><Development><Dextrose><Diet><Digestive Tract><Disease><Disorder><ER stress><Embryo Deaths><Enzyme Gene><Enzymes><Ethanal><Ethanol Metabolism><Exposure to><Fats><Fatty acid glycerol esters><Fetal Alcohol Syndrome><Fetal Death><Fibrosis><Future><GI Tract><Gastrointestinal Tract><Gastrointestinal tract structure><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic Diversity><Genetic Transcription><Genetic Variation><Genome Instability><Genomic Instability><Glucose><Hepatic Cancer><Hepatic Cells><Hepatic Disorder><Hepatic Parenchymal Cell><Hepatic Transplantation><Hepatocarcinoma><Hepatocellular Carcinoma><Hepatocellular cancer><Hepatocyte><Hepatoma><Heterozygote><Human><ICE-like protease><Immune><Immune system><Immunes><Impairment><Inflammation><Injury to Liver><Intervention><Intervention Strategies><Intracellular Communication and Signaling><JV15-2><KO mice><Knock-out><Knock-out Mice><Knockout><Knockout Mice><Length><Lipids><Liver><Liver Cells><Liver Cells Carcinoma><Liver Grafting><Liver Transplant><Liver diseases><MADH3><MADH3 gene><Macrophage-Derived TNF><Malignant neoplasm of liver><Mediating><Metabolic><Metabolic syndrome><Mice><Mice Mammals><Milk Growth Factor><Mitochondria><Modern Man><Modification><Molecular><Molecular Interaction><Monocyte-Derived TNF><Mothers Against Decapentaplegic, Drosophila, Homolog of, 3><Murine><Mus><Mutant Strains Mice><NAFLD><NASH><Null Mouse><Obesity><Oncogenesis><Oncogenic><Outcome><PARP Cleavage Protease><PARP Cleavage Protease Gene><Pathologic><Pathology><Pathway interactions><Patients><Persons><Phenotype><Platelet Transforming Growth Factor><Play><Population><Predisposition><Primary carcinoma of the liver cells><Process><Proteins><Publishing><RNA Expression><Reducing diet><Risk Factors><Role><SCA-1><SCA-1 Gene><SMA- and MAD-Related Protein 3><SMAD3><SRE-1 binding protein><SREBP Cleavage Activity 1><SREBP Cleavage Activity 1 Gene><SREBP-1><Sampling><Short interfering RNA><Signal Transduction><Signal Transduction Systems><Signaling><Single Base Polymorphism><Single Nucleotide Polymorphism><Small Interfering RNA><Spectrin><Strains Cell Lines><Stress><Susceptibility><System><TGF B><TGF-beta><TGF-β><TGFbeta><TGFβ><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Testing><Therapeutic><Therapeutic Intervention><Tissues><Transcription><Transcription Activation><Transcription Factor Proto-Oncogene><Transcription factor genes><Transcriptional Activation><Transforming Growth Factor beta><Transforming Growth Factor-Beta Family Gene><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><United States><Unscheduled DNA Synthesis><Yama><Yama protein><adduct><adipogenesis><adiposity><alcohol induced hepatic injury><alcohol induced liver disorder><alcohol induced liver injury><alcohol metabolism><alcohol related liver disease><alcohol sensitivity><alcohol-associated liver disease><alcohol-induced hepatic dysfunction><alcohol-induced liver disease><alcohol-induced liver dysfunction><alcohol-mediated liver dysfunction><alcohol-mediated liver injury><alcohol-related liver disease><alcoholic embryopathy><alcoholic liver injury><aldehyde dehydrogenases><alimentary tract><beta Spectrin><biological signal transduction><caspase-3><chronic hepatic disease><chronic hepatic disorder><chronic liver disease><chronic liver disorder><corpulence><cultured cell line><cystein protease><cystein proteinase><cysteine endopeptidase><cysteine protease P32><developmental><diets><digestive canal><embryofetal alcohol syndrome><embryopathia alcoholica><endoplasmic reticulum stress><ethanol induced hepatic injury><ethanol induced liver disorder><ethanol induced liver injury><ethanol liver disease><ethanol sensitivity><ethanol-induced hepatic dysfunction><ethanol-induced liver disease><ethanol-induced liver dysfunction><ethanol-mediated liver dysfunction><ethanol-mediated liver injury><fat metabolism><fatty liver disease><fetus death><gastrointestinal homeostasis><hepatic body system><hepatic damage><hepatic disease><hepatic injury><hepatic organ system><hepatopathy><heterozygosity><improved><intervention therapy><interventional strategy><intestinal homeostasis><knock-down><knockdown><knockout gene><lipid biosynthesis><lipid metabolism><lipogenesis><liver cancer><liver carcinoma><liver damage><liver development><liver disorder><liver injury><liver malignancy><liver transplantation><malignant liver tumor><mitochondrial><mouse model><mouse mutant><murine model><non-alcohol fatty liver disease><non-alcohol induced steatohepatitis><non-alcoholic fatty liver disease><non-alcoholic liver disease><non-alcoholic steato-hepatitis><non-alcoholic steatohepatitis><nonalcoholic fatty liver disease><nonalcoholic steato-hepatitis><nonalcoholic steatohepatitis><novel><pathway><prevent><preventing><progenitor cell markers><progenitor markers><progenitor stem cell markers><sensitivity to alcohol><sensitivity to ethanol><siRNA><single nucleotide variant><social role><stem cell biomarkers><stem cell markers><sterol regulatory element-binding protein 1><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><telomere><three dimensional><transcription factor><tumorigenesis><western diet><western-style diet><western-type diet><β-Spectrin>