David W. Crabb, MD
Professor of Medicine
I have been involved in alcoholism and liver research since the early 1980’s. This has included the study of effects of ethanol on intermediary metabolism in the liver and adipocytes, using cultured cells, and in vivo animal and human models. In addition, I have been closely involved in studies on the genetics of alcoholism, the epidemiology of alcohol use disorders, and human and animal studies of responses to alcohol, through my role as Director of the Indiana Alcohol Research Center. The Center has been funded for three decades.
We discovered that ethanol inhibits the activity of PPARα, activates SREBP1c, and inhibits AMP-dependent protein kinase (AMPK) in liver. The changes in the transcription factors and AMPK make the liver less capable of oxidizing fatty acids and induce fatty acid synthesizing enzymes. The inhibition of AMPK results in increased acetyl-CoA carboxylase activity and malonyl-CoA levels, blocking the ability of fatty acyl-CoA to enter the mitochondrion. More recently we have uncovered effects of alcohol use on ChREBP, which is relevant to the development of fatty liver from both alcohol and diet, and ceramide and protein phosphatase 2 (PP2A) that have implications for activation of stress kinases, and inhibition of anti-apoptotic pathways. These actions of alcohol on nuclear receptor signaling and stress kinases are directly relevant to the pathogenesis of alcoholic steatosis, alcoholic hepatitis, and likely to other forms of fatty liver, such as those related to obesity and diabetes (NAFLD and NASH) and to drug toxicity.
My involvement in the care of patients with alcoholism, research on pathogenesis of alcoholic liver injury, and my hepatology training led to involvement in organizing a multi-center consortium funded by the NIAAA to study the natural history and treatments for alcoholic hepatitis (TREAT: Translational Research and Evolving Alcoholic hepatitis Treatment) as well as performing mechanistic studies on the pathways leading to severe liver injury in human subjects. In addition, I have been involved in implementing screening for hazardous alcohol use (screening, brief intervention and referral to treatment) across the Eskenazi Health system.
Web Address: http://medicine.iupui.edu/IARC
Titles & Appointments
- Professor of Biochemistry & Molecular Biology
- Chief of Internal Medicine at Eskenazi Health Hospital
Alcohol metabolism, Liver Gene Expression.
Standard Definitions and Common Data Elements for Clinical Trials in Patients With Alcoholic Hepatitis: Recommendation From the NIAAA Alcoholic Hepatitis Consortia.
The Utility of Commonly Used Laboratory Tests to Screen for Excessive Alcohol Use in Clinical Practice.
Increasing serum pre-adipocyte factor-1 (Pref-1) correlates with decreased body fat, increased free fatty acids, and level of recent alcohol consumption in excessive alcohol drinkers.
Ethanol metabolism by HeLa cells transduced with human alcohol dehydrogenase isoenzymes: control of the pathway by acetaldehyde concentration.
Imipramine blocks ethanol-induced ASMase activation, ceramide generation, and PP2A activation, and ameliorates hepatic steatosis in ethanol-fed mice.
Inhibitory effect of ethanol on AMPK phosphorylation is mediated in part through elevated ceramide levels.
Relationship between alcohol drinking and aspartate aminotransferase:alanine aminotransferase (AST:ALT) ratio, mean corpuscular volume (MCV), gamma-glutamyl transpeptidase (GGT), and apolipoprotein A1 and B in the U.S. population.
A proteomic workflow for discovery of serum carrier protein-bound biomarker candidates of alcohol abuse using LC-MS/MS.
Association of the aldehyde dehydrogenase 2 promoter polymorphism with alcohol consumption and reactions in an American Jewish population.
Acetaldehyde generating enzyme systems: roles of alcohol dehydrogenase, CYP2E1 and catalase, and speculations on the role of other enzymes and processes.
Protein expression changes in the nucleus accumbens and amygdala of inbred alcohol-preferring rats given either continuous or scheduled access to ethanol.
Global effects of vitamin A deficiency on gene expression in rat liver: evidence for hypoandrogenism.
Role of adiponectin in the protective action of dietary saturated fat against alcoholic fatty liver in mice.
Recent advances in alcoholic liver disease II. Minireview: molecular mechanisms of alcoholic fatty liver.
Overview of the role of alcohol dehydrogenase and aldehyde dehydrogenase and their variants in the genesis of alcohol-related pathology.
Systemic levels of lipid peroxidation and its metabolic and dietary correlates in patients with nonalcoholic steatohepatitis.
Molecular mechanisms of alcoholic fatty liver: role of peroxisome proliferator-activated receptor alpha.
Peroxisome proliferator-activated receptor alpha (PPARalpha) agonist treatment reverses PPARalpha dysfunction and abnormalities in hepatic lipid metabolism in ethanol-fed mice.
Innate differences in protein expression in the nucleus accumbens and hippocampus of inbred alcohol-preferring and -nonpreferring rats.
Metabolic and anthropometric evaluation of insulin resistance in nondiabetic patients with nonalcoholic steatohepatitis.
Ethanol induces fatty acid synthesis pathways by activation of sterol regulatory element-binding protein (SREBP).
Peroxisome proliferator-activated receptors (PPAR) and the mitochondrial aldehyde dehydrogenase (ALDH2) promoter in vitro and in vivo.
The transcriptional and DNA binding activity of peroxisome proliferator-activated receptor alpha is inhibited by ethanol metabolism. A novel mechanism for the development of ethanol-induced fatty liver.
Effects of vitamin A deficiency on rat liver alcohol dehydrogenase expression and alcohol elimination rate in rats.
Sensitivity of virally-driven luciferase reporter plasmids to members of the steroid/thyroid/retinoid family of nuclear receptors.
An A/G polymorphism in the promoter of mitochondrial aldehyde dehydrogenase (ALDH2): effects of the sequence variant on transcription factor binding and promoter strength.
Binding and activation of the human aldehyde dehydrogenase 2 promoter by hepatocyte nuclear factor 4.
A direct repeat (DR-1) element in the first exon modulates transcription of the preproenkephalin A gene.
Structural and mechanistic aspects of a new family of dehydrogenases, the beta-hydroxyacid dehydrogenases.
The role of nuclear factor NF-Y/CP1 in the transcriptional regulation of the human aldehyde dehydrogenase 2-encoding gene.
The mutation in the mitochondrial aldehyde dehydrogenase (ALDH2) gene responsible for alcohol-induced flushing increases turnover of the enzyme tetramers in a dominant fashion.
Dexamethasone represses phorbol ester-, forskolin-, and calcium-stimulated expression of a preproenkephalin A promoter-chloramphenicol acetyltransferase gene via a receptor-mediated mechanism.
Structural and mechanistic similarities of 6-phosphogluconate and 3-hydroxyisobutyrate dehydrogenases reveal a new enzyme family, the 3-hydroxyacid dehydrogenases.
Distribution of messenger RNAs for aldehyde dehydrogenase 1, aldehyde dehydrogenase 2, and aldehyde dehydrogenase 5 in human tissues.
Hormonal and chemical influences on the expression of class 2 aldehyde dehydrogenases in rat H4IIEC3 and human HuH7 hepatoma cells.
Chemical modification and site-directed mutagenesis studies of rat 3-hydroxyisobutyrate dehydrogenase.
Tissue-specific expression and preliminary functional analysis of the 5' flanking regions of the human mitochondrial aldehyde dehydrogenase (ALDH2) gene.
Allele frequencies of the preproenkephalin A (PENK) gene CA repeat in Asians, African-Americans, and Caucasians: lack of evidence for different allele frequencies in alcoholics.
Site-directed mutagenesis of phosphorylation sites of the branched chain alpha-ketoacid dehydrogenase complex.
Seven transmembrane domain receptor subtypes identified in NG108-15 cells by reverse transcription-polymerase chain reaction.
Intrasplenic transplantation of isolated periportal and perivenous hepatocytes as a long-term system for study of liver-specific gene expression.
Alcohol sensitivity, alcohol metabolism, risk of alcoholism, and the role of alcohol and aldehyde dehydrogenase genotypes.
The mitochondrial aldehyde dehydrogenase gene resides in an HTF island but is expressed in a tissue-specific manner.
Primary structure of pyruvate dehydrogenase kinase establishes a new family of eukaryotic protein kinases.
Modulation of hepatic and renal alcohol dehydrogenase activity and mRNA by steroid hormones in vivo.
Molecular cloning of the branched-chain alpha-keto acid dehydrogenase kinase and the CoA-dependent methylmalonate semialdehyde dehydrogenase.
CoA-dependent methylmalonate-semialdehyde dehydrogenase, a unique member of the aldehyde dehydrogenase superfamily. cDNA cloning, evolutionary relationships, and tissue distribution.
Estradiol regulates class I alcohol dehydrogenase gene expression in renal medulla of male rats by a post-transcriptional mechanism.
Molecular defects in the E1 alpha subunit of the branched-chain alpha-ketoacid dehydrogenase complex that cause maple syrup urine disease.
Endocrine regulation and methylation patterns of rat class I alcohol dehydrogenase in liver and kidney.
Premature translation termination of the pre-E1 alpha subunit of the branched chain alpha-ketoacid dehydrogenase as a cause of maple syrup urine disease in Polled Hereford calves.
Sequence of the E1 alpha subunit of branched-chain alpha-ketoacid dehydrogenase in two patients with thiamine-responsive maple syrup urine disease.
Regulation of the branched-chain alpha-ketoacid dehydrogenase and elucidation of a molecular basis for maple syrup urine disease.
Genotypes for aldehyde dehydrogenase deficiency and alcohol sensitivity. The inactive ALDH2(2) allele is dominant.
Cloning and sequence analysis of a cDNA for 3-hydroxyisobutyrate dehydrogenase. Evidence for its evolutionary relationship to other pyridine nucleotide-dependent dehydrogenases.
Evidence for both a regulatory mutation and a structural mutation in a family with maple syrup urine disease.
Localization of the human gene for the El alpha subunit of branched chain keto acid dehydrogenase (BCKDHA) to chromosome 19q13.1----q13.2.
Assignment of the gene for the E1 alpha subunit of branched chain alpha-ketoacid dehydrogenase to chromosome 19.
cDNA cloning of the E1 alpha subunit of the branched-chain alpha-keto acid dehydrogenase and elucidation of a molecular basis for maple syrup urine disease.
Nucleotide and deduced amino acid sequence of the E1 alpha subunit of human liver branched-chain alpha-ketoacid dehydrogenase.
Molecular cloning of a cDNA for the E1 alpha subunit of rat liver branched chain alpha-ketoacid dehydrogenase.
Eskenazi Community Outreach Program.
Association of American Physicians
American Board of Internal Medicine - Gastroenterology