Skip to main content
ARS Home » Southeast Area » Little Rock, Arkansas » Arkansas Children's Nutrition Center » Research » Publications at this Location » Publication #319034

Title: N-acetylcysteine inhibits the up-regulation of mitochondrial biogenesis genes in livers from rats fed ethanol chronically

Author
item CARO, ANDRES - Hendrix College
item BELL, MATTHEW - Hendrix College
item EJIOFOR, SHANNON - Hendrix College
item ZURCHER, GRANT - Hendrix College
item PETERSEN, DENNIS - University Of Colorado
item RONIS, MARTIN - Arkansas Children'S Nutrition Research Center (ACNC)

Submitted to: Alcoholism: Clinical and Experimental
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/6/2014
Publication Date: 12/1/2014
Citation: Caro, A.A., Bell, M., Ejiofor, S., Zurcher, G., Petersen, D.R., Ronis, M.J. 2014. N-acetylcysteine inhibits the up-regulation of mitochondrial biogenesis genes in livers from rats fed ethanol chronically. Alcoholism: Clinical and Experimental. 38(12):2896-2906.

Interpretive Summary: Alcohol abuse results in progressive liver injury often requiring a liver transplant. A major alcohol target in liver cells is the mitochondria. Mitochondria are the energy generator in cells and mitochondrial injury often produces cell death. However, if the injury is at a lower level, mitochondria are able to adapt by dividing and generating a larger number of organelles. This process is known as mitochondrial biogenesis. Alcohol feeding results in mitochondrial biogenesis. However, the molecular mechanisms underlying this phenomenon have not been fully explored. In this paper, we tested the possibility that oxidativestress is the factor that triggers mitochondrial biogenesis after alcohol feeding. If our idea is correct,co-administration of dietary antioxidants with alcohol should prevent up-regulation of mitochondrial biogenesis genes.Rats were fed an alcohol diet through a stomach tube for 150 days, in the absence or presence of the antioxidant N-acetylcysteine (NAC) at 1.7 g/kg/d; controlrats were administered control diets where carbohydrates substituted for EtOH calories.Alcohol increased the expression of mitochondrial biogenesis genes and NAC prevented these effects. Alcohol also decreased mitochondrial mass, damaged energy production, and increased mitochondrial oxidative damage, effects that were not prevented by NAC. Conclusions: These results suggest that oxidative stress caused by chronic EtOH triggered the upregulation of mitochondrial biogenesis because an antioxidant such as NAC blocked the effect. In spite of the induction of mitochondrial biogenesis mitochondrial mass and function decreased after alcohol consumption probably in association with mitochondrial oxidative damage. These results also predict that the effectiveness of NAC as an antioxidant therapy for liver injury in alcoholics will be limited by its limited antioxidant effects in mitochondria, and its inhibitory effect on mitochondrial biogenesis.

Technical Abstract: Background: Chronic ethanol (EtOH) administration to experimental animals induces hepatic oxidative stress and up-regulates mitochondrial biogenesis. The mechanisms by which chronic EtOH up-regulates mitochondrial biogenesis have not been fully explored. In this work, we hypothesized that oxidative stress is a factor that triggersmitochondrial biogenesis after chronic EtOH feeding. If our hypothesis is correct,co-administration of antioxidants should prevent up-regulation ofmitochondrial biogenesis genes. Methods: Rats were fed an EtOH-containing diet intragastrically by total enteral nutrition for 150 days, in the absence or presence of the antioxidant N-acetylcysteine (NAC) at 1.7 g/kg/d; control rats were administered isocaloric diets where carbohydrates substituted for EtOH calories. Results: EtOH administration significantly increased hepatic oxidative stress, evidenced as decreased liver total glutathione and reduced glutathione/glutathione disulfide ratio. These effects were inhibited by co-administration of EtOH and NAC. Chronic EtOH increased the expression of mitochondrial biogenesis genes including peroxisome proliferator-activated receptor gamma-coactivator-1 alpha and mitochondrial transcription factor A, and mitochondrial DNA; co-administration of EtOH and NAC prevented these effects. Chronic EtOH administration was associated with decreased mitochondrial mass, inactivation and depletion of mitochondrial complex I and complex IV, and increased hepatic mitochondrial oxidative damage, effects that were not prevented by NAC. Conclusions: These results suggest that oxidative stress caused by chronic EtOH triggered the upregulation of mitochondrial biogenesis genes in rat liver, because an antioxidant such as NAC prevented both effects. Because NAC did not prevent liver mitochondrial oxidative damage, extra-mitochondrial effects of reactive oxygen species may regulate mitochondrial biogenesis. In spite of the induction of hepatic mitochondrial biogenesis genes by chronic EtOH, mitochondrial mass and function decreased probably in association with mitochondrial oxidative damage. These results also predict that the effectiveness of NAC as an antioxidant therapy for chronic alcoholism will be limited by its limited antioxidant effects in mitochondria, and its inhibitory effect on mitochondrial biogenesis.