Molecular Pathogenesis of Alcoholic Liver Disease

Project Leader: Professor Geoffrey McCaughan
Research conducted by: Dr Devanshi Seth and Professor Paul Haber

Recent government and community attention on alcohol related problems highlight its significance as a cause of morbidity and mortality.

Alcoholic liver disease (ALD) is the leading cause of alcohol related death and contributes to 50% of the total burden of liver disease and to 15% of liver transplants. Once the disease is established, abstinence from alcohol use is the only intervention that is associated with improved outcomes. At present, there is no other widely accepted treatment.

ALD is a complex disorder. Many years of regular and excessive drinking lead to a pathological spectrum from alcoholic steatosis to alcoholic hepatitis, liver fibrosis and cirrhosis. Ethanol initiates liver injury by generation of oxidative and non-oxidative ethanol metabolites and via endotoxin leading to cellular injury and inflammation. Alcoholic steatosis (fatty liver) was considered a benign lesion with a favourable prognosis on alcohol abstinence but recent studies show that inflammatory changes signify an increased risk for more serious liver disease. With continuing alcohol use, the disease progresses via impairment of hepatic regeneration, and increasing fibrogenesis leading to cirrhosis and its complications. Chronic alcoholic liver injury also increases the risk of liver cancer.

The progression of ALD is influenced by various factors such as gender, nutrition, viral infection and iron overload. Nonetheless, the genetic and molecular factors that underlie progression to alcoholic hepatitis and cirrhosis are not well understood. Nor is it known why only a minority of heavy drinkers progress to alcoholic cirrhosis. Several groups have sought evidence for an underlying genetic basis for this susceptibility but this remains unproven.

Research focus

This is a unique research project as there are few groups in Australia working on identifying biomarkers and genetic risk factors for ALD. This project has been established as a strategic partnership with Professor Geoff McCaughan at the Centenary Institute, AW Morrow Gastroenterology & Liver Centre and Professor Haber and Dr Seth at the Drug Health Services resulting in several peer-reviewed publications with other collaborators at the Centenary Institute (Drs Mark Gorrell & Nick Shackel). The current research priorities are to address mechanisms and pathways of two lead molecules identified in the first stage of this project as potential diagnostic and therapeutic targets. In addition, projects on genetic risk factors associated with ALD are also in early stages of development. The following projects are offered for Honours and PhDs.

The diagnostic and therapeutic significance of Osteopontin (Opn) isoforms in liver disease and cancer
We have recently reported that Opn (a molecule involved in inflammation and celluar activity), and several Opn receptors were up-regulated in human ALD.(2) We have cloned three Opn isoforms and have shown that they are involved in liver cell growth, migration and tumor development. Our current studies are investigating the precise mechanisms of Opn action by using molecular and cellular techniques (Opn knockouts, Opn si RNA, signalling transduction) in collaboration with leading scientific colleagues at the University of Sydney (F Braet), University of Adelaide (M Beard) and National Centre for Cell Science, India (G Kundu). These studies aim to define molecules that may be used as markers of disease severity or as targets for development of new treatments.

The role of plasmin and the fibrinolysis pathway in the progression of alcohol- mediated liver injury
We have identified alterations affecting several molecules that influence the breakdown of fibrin in the liver (fibrinolysis) of humans with ALD.(1) We have shown that two of these molecules (annexin A2 and plasminogen activator inhibitor-1) play a role in regulating fibrinolysis in alcoholic liver injury. We are currently using specific inhibitors of these molecules to study the possible therapeutic advantage of these targets. These studies involve collaborations with a number of leading scientists including Professor Phil Hogg (University of NSW) and Professor Mathew Vadas.

Genetic risk factors for ALD
We have established an international collaborative working group with lead alcohol researchers to create a genome wide association consortium to study the genetic risk factors in heavy drinkers for alcoholic liver disease. Dr Devanshi Seth is leading the Australian involvement by coordinating this group and seeking approval from NIH/National Institute for Alcohol Abuse and Alcoholism (NIAAA) to fund this study. This is to be the first study of its kind in ALD and has attracted well known alcohol researchers from the USA, UK, Germany, France, Switzerland and Australia.

We have in vitro hepatic cell culture models of alcohol that are utilised in functional assays to study mechanisms of action of select molecules. We also have in vivo mouse models for chronic and acute alcohol (single and multiple binge) for studying mechanisms of alcohol induced pathogenesis. The various animal models represent the three major modes of alcohol drinking patterns in human and will be significant in comparing and identifying alcohol induced injuries within this spectrum.

Key Publications

1. Seth D, Hogg P, Gorrell MD, McCaughan GW, Haber PS. Direct effects of alcohol on hepatic fibrinolytic balance: implications for alcoholic liver disease. J Hepatol. 2008; 48(4):614-627. doi:10.1016/j.jhep.2007.12.015. [IF: 6.64]

2. Seth D, Cordoba S, Gorrell MD, McCaughan GW, Haber PS. Intrahepatic Gene Expression in Human Alcoholic Hepatitis. J Hepatology. 2006; 45:306-320. [IF: 6.64]

3. Seth D, Maria A. Leo, Peter H. McGuinness, Charles S. Lieber, Brennan Y, Williams R, Wang XM, McCaughan GW, Gorrell MD, Haber PS. Gene Expression Profiling of Alcoholic Liver Disease in the Baboon (Papio hamadryas) and Human Liver. Am J Path. 2003; 163 (6): 2303-2317. [IF: 6.441]

4. Shackel N, Seth D, Williams RW, Gorrell MD, Haber PS, McCaughan GW. The hepatic transcriptome in human liver disease. Comparative Hepatology. 2006; 5:6-54. MS ID: 1156958295883026. Review.

5. Neuman MG, Sha K, Esguerra1 R, Winkler RE, Cooper CL, Hilzenrat N, Wise J, Zakhari S, Seth D, Gorrell MD, Haber PS, McCaughan GW, Leo MA, Lieber CS, Voiculescu M, Buzatu E, Ionescu C, Dudas J, Saile B. Ramadori G. Inflammation and Repair in Viral Hepatitis C. Dig Dis Sci. 2008; 53(6):1468-87. PMID: 17994278. [IF:1.32]

For more publication information, please contact Dr Seth or Professor Haber, or search the available listings on PubMed.