Skip to main content
Article thumbnail
Location of Repository

Effect of chronic ethanol exposure on the liver of Clock-mutant mice

By Takashi Kudo, Toru Tamagawa and Shigenobu Shibata


In humans, chronic ethanol consumption leads to a characteristic set of changes to the metabolism of lipids in the liver that is referred to as an "alcoholic fatty liver (AFL)". In severe cases, these metabolic changes result in the enlargement and fibrillization of the liver and are considered risk factors for cirrhosis and liver cancer. Clock-mutant mice have been shown to display abnormal lipid metabolism and alcohol preferences. To further understand the potential interactions between ethanol consumption, lipid metabolism, and the circadian clock, we investigated the effect of chronic ethanol intake on the lipid metabolism of Clock-mutant mice. We found that ethanol treatment produced a number of changes in the liver of Clock-mutant mice without impacting the wild-type controls. First, we found that 8 weeks of exposure to ethanol in the drinking water increased the weight of the liver in Clock-mutant mice. Ethanol treatment also increased triglyceride content of liver in Clock-mutant and wild-type mice. This increase was larger in the mutant mice. Finally, ethanol treatment altered the expression of a number of genes related to lipid metabolism in the Clock-mutant mice. Interestingly, this treatment did not impact circadian clock gene expression in the liver of either genotype. Thus, ethanol produces a number of changes in the liver of Clock-mutant mice that are not seen in the wild-type mice. These changes are consistent with the possibility that disturbance of circadian rhythmicity associated with the Clock mutation could be a risk factor for the development of an alcoholic fatty liver

Topics: Research
Publisher: BioMed Central
OAI identifier:
Provided by: PubMed Central

Suggested articles


  1. (2002). A transcription factor response element for gene expression during circadian night. Nature
  2. (2007). A: Alcoholic and nonalcoholic forms of fatty liver disease. Minerva Gastroenterol Dietol
  3. (1971). Alcohol and the liver. Gut
  4. (2004). Aoyama T: Peroxisome proliferator-activated receptor alpha protects against alcoholinduced liver damage. Hepatology
  5. (2001). Biochemical detection and monitoring of alcohol abuse and abstinence. Ann Clin Biochem
  6. (2007). Carrilho FJ: Nonalcoholic steatohepatitis (NASH) in ob/ob mice treated with yo jyo hen shi ko (YHK): effects on peroxisome proliferator-activated receptors (PPARs) and microsomal triglyceride transfer protein (MTP). Dig Dis Sci
  7. (2007). Chaichantipyuth C: Hepatoprotective activity of Phyllanthus amarus Schum. et. Thonn. extract in ethanol treated rats: in vitro and in vivo studies.
  8. (2007). Clock mutation facilitates accumulation of cholesterol in the liver of mice fed a cholesterol/cholic acid diet.
  9. (2006). DE: Modulation of fatty acid metabolism as a potential approach to the treatment of obesity and the metabolic syndrome. Endocrine
  10. (2007). Diabetes mellitus and macrovascular disease: mechanisms and mediators.
  11. (2008). Dysregulation of systemic iron metabolism in alcoholic liver diseases.
  12. (2005). et al.: CLOCK/BMAL1 is involved in lipid metabolism via transactivation of the peroxisome proliferator-activated receptor (PPAR) response element. J Atheroscler Thromb
  13. (2003). Genome-wide expression analysis of mouse liver reveals CLOCK-regulated circadian output genes.
  14. (1998). Hara K: Expression of cytokine mRNA in extrahepatic organs in a mouse concanavalin A-hepatitis model.
  15. (1987). Hepatic triacylglycerol accumulation induced by ethanol and carbon tetrachloride: interactions with essential fatty acids and prostaglandins. Alcohol Clin Exp Res
  16. (1981). Hepatocyte demand and substrate supply as factors in the susceptibility to alcoholic liver injury: pathogenesis and prevention. Clin Gastroenterol
  17. (2002). Hogenesch JB: Coordinated transcription of key pathways in the mouse by the circadian clock. Cell
  18. (1990). JL: Dietinduced hypercholesterolemia in mice: prevention by overexpression of LDL receptors.
  19. (2004). JS: Circadian clock mutation disrupts estrous cyclicity and maintenance of pregnancy. Curr Biol
  20. (2006). MH: Developmental and reproductive performance in circadian mutant mice. Hum Reprod
  21. (2007). Molecular diversity and evolution of the large lipid transfer protein superfamily.
  22. (1994). Mutagenesis and mapping of a mouse gene, Clock, essential for circadian behavior. Science
  23. (2005). Obesity and metabolic syndrome in circadian Clock mutant mice. Science
  24. (2008). Overproduction of very low-density lipoproteins is the hallmark of the dyslipidemia in the metabolic syndrome. Arterioscler Thromb Vasc Biol
  25. (2006). Overview: how is alcohol metabolized by the body? Alcohol Res Health
  26. (2008). Pari L: Caffeic acid alleviates the increased lipid levels of serum and tissues in alcohol-induced rats. Fundam Clin Pharmacol
  27. (2007). Pathology of nonalcoholic fatty liver disease.
  28. (2007). Pirola CJ: Common genetic variations in CLOCK transcription factor are associated with nonalcoholic fatty liver disease.
  29. (1997). Positional cloning of the mouse circadian clock gene. Cell
  30. (1980). RC: Circadian rhythms in the biological response and disposition of ethanol in the mouse. J Pharmacol Exp Ther
  31. (2006). Reppert SM: A clock shock: mouse CLOCK is not required for circadian oscillator function. Neuron
  32. (2007). Reppert SM: Peripheral circadian oscillators require CLOCK. Curr Biol
  33. (2000). Rhythmic expression of BMAL1 mRNA is altered in Clock mutant mice: differential regulation in the suprachiasmatic nucleus and peripheral tissues. Biochem Biophys Res Commun
  34. (2007). Sassone-Corsi P: CLOCK-mediated acetylation of BMAL1 controls circadian function. Nature
  35. (2004). Sex differences in the vulnerability to drug abuse: a review of preclinical studies. Neurosci Biobehav Rev
  36. (2008). SM: Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases. Free Radic Biol Med
  37. (2005). System-level identification of transcriptional circuits underlying mammalian circadian clocks. Nat Genet
  38. (2007). Takase S : Effect of the inducer of interleukin-6 (ME3738) on rat liver treated with ethanol. Alcohol Clin Exp Res
  39. (1990). The circadian rhythm of intra-acinar profiles of alcohol dehydrogenase activity in rat liver: a microquantitative study. Histochem J
  40. (2005). The role of circadian rhythmicity in reproduction. Hum Reprod Update
  41. (1993). Wahli W: Peroxisome proliferator-activated receptors and lipid metabolism.

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.