The Role of Oxidative Stress in Alcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis of Preclinical Studies

Abstract

Alcoholic Fatty Liver Disease (AFLD) is characterized by the accumulation of lipids in liver cells owing to the metabolism of ethanol. This process leads to a decrease in the NAD⁺/NADH ratio and the generation of reactive oxygen species. A systematic review and meta-analysis were conducted to investigate the role of oxidative stress in AFLD. A total of 201 eligible manuscripts were included, which revealed that animals with AFLD exhibited elevated expression of CYP2E1, decreased enzymatic activity of antioxidant enzymes, and reduced levels of the transcription factor Nrf2, which plays a pivotal role in the synthesis of antioxidant enzymes. Furthermore, animals with AFLD exhibited increased levels of lipid peroxidation markers and carbonylated proteins, collectively contributing to a weakened antioxidant defense and increased oxidative damage. The liver damage in AFLD was supported by significantly higher activity of alanine and aspartate aminotransferase enzymes. Moreover, animals with AFLD had increased levels of triacylglycerol in the serum and liver, likely due to reduced fatty acid metabolism caused by decreased PPAR-α expression, which is responsible for fatty acid oxidation, and increased expression of SREBP-1c, which is involved in fatty acid synthesis. With regard to inflammation, animals with AFLD exhibited elevated levels of pro-inflammatory cytokines, including TNF-a, IL-1β, and IL-6. The heightened oxidative stress, along with inflammation, led to an upregulation of cell death markers, such as caspase-3, and an increased Bax/Bcl-2 ratio. Overall, the findings of the review and meta-analysis indicate that ethanol metabolism reduces important markers of antioxidant defense while increasing inflammatory and apoptotic markers, thereby contributing to the development of AFLD.

Keywords: alcoholic steatosis; antioxidant enzymes; apoptosis; inflammation; lipid peroxidation.

Figure 1

Flow diagram of the study selection process for this systematic review and meta-analysis.

Figure 2

Evidence of decreased superoxide dismutase (SOD) activity in liver tissue. The forest plot indicates lower SOD activity in the livers of animals with alcoholic fatty liver disease (AFLD) compared with healthy controls (p < 0.05 for each). 95% Cl: confidence interval.

Figure 3

Forest plot showing the decrease in catalase (CAT) activity in liver tissue from animals with alcoholic fatty liver disease (AFLD) compared with healthy controls (p < 0.05 for each). The 95% confidence interval is also shown.

Figure 4

Forest plot showing glutathione peroxidase (GPx) activity in liver tissue. There is evidence of decreased GPx activity in the liver tissue of animals with alcoholic fatty liver disease (AFLD) compared with healthy controls (p < 0.05). 95% Cl: confidence interval.

Figure 5

Forest plot showing the results of combining studies that analyzed glutathione reductase (GR) activity in the liver. Animals with alcoholic fatty liver disease (AFLD) had lower GR activity compared with healthy controls (p < 0.05). 95% Cl: confidence interval.

Figure 6

The evidence suggests a decrease in glutathione transferase (GST) activity in the liver tissue of animals with alcoholic fatty liver disease (AFLD) compared with healthy controls. This is supported by the forest plot, which shows a significant reduction in GST activity (p < 0.05 for each), with 95% confidence intervals (Cl) reported.

Figure 7

The evidence suggests a decrease in reduced glutathione (GSH) in the liver tissue of animals with alcoholic fatty liver disease (AFLD) compared with healthy controls. This is supported by the forest plot, which shows a significant reduction in GSH (p < 0.05 for each), with 95% confidence intervals (Cl) reported.

Figure 8

Analysis of the reduced glutathione (GSH)/oxidized glutathione (GSSG) ratio in the livers of rats with AFLD and control groups. The forest plot shows that the AFLD groups had reduced GSH/GSSG ratios compared with the control group (p < 0.05 for each), with 95% confidence intervals (Cl) reported.

Figure 9

Analysis of lipid peroxidation in the livers of rats with AFLD and healthy controls. The forest plot shows that AFLD groups had increased lipid peroxidation compared with control groups (p < 0.05 for each), with 95% confidence intervals (Cl) reported.

Figure 10

Analysis of protein carbonyl in the livers of rats with AFLD and healthy controls. The forest plot shows that AFLD groups had increased protein carbonyl levels compared with control groups (p < 0.05 for each), with 95% confidence intervals (Cl) reported.