Acute Kidney Injury Induces Oxidative Stress and Hepatic Lipid Accumulation through AMPK Signaling Pathway

Acute kidney injury (AKI) often impairs the function of other organs leading to distant organ injury. The liver is the major organ that regulates metabolism and lipid homeostasis in the body. It has been reported that AKI causes liver injury with increased oxidative stress, inflammatory response and steatosis. In the present study, we investigated the mechanisms by which ischemia-reperfusion-induced AKI caused hepatic lipid accumulation. Kidney ischemia (45 min)-reperfusion (24 h) led to a significant increase in plasma creatinine and transaminase in Sprague Dawley rats, indicating kidney and liver injury. Histological and biochemical analyses revealed hepatic lipid accumulation with a significant elevation of triglyceride and cholesterol levels in the liver. This was accompanied by a decreased AMP-activated protein kinase (AMPK) phosphorylation, indicating the reduced activation of AMPK, which is an energy sensor that regulates lipid metabolism. The expression of AMPK-regulated genes that were responsible for fatty acid oxidation (CPTI alpha, ACOX) was significantly decreased, while the expression of lipogenesis genes (SREPB-1c, ACC1) was significantly elevated. The oxidative stress biomarker malondialdehyde was elevated in the plasma and liver. Incubation of HepG2 cells with an oxidative stress inducer hydrogen peroxide inhibited AMPK phosphorylation and caused cellular lipid accumulation. This was accompanied by decreased expression of genes responsible for fatty acid oxidation and increased expression of genes responsible for lipogenesis. These results suggest that AKI elicits hepatic lipid accumulation through decreased fatty acid metabolism and increased lipogenesis. Oxidative stress may contribute, in part, to the downregulation of the AMPK signaling pathway leading to hepatic lipid accumulation and injury.

Automated summary

Acute kidney injury (AKI) often leads to liver injury with increased oxidative stress, inflammatory response, and lipid accumulation. The mechanisms by which ischemia-reperfusion-induced AKI causes hepatic lipid accumulation were investigated in this study. Kidney ischemia-reperfusion resulted in kidney and liver injury, as indicated by increased plasma creatinine and transaminases. Histological and biochemical analysis revealed hepatic lipid accumulation with increased triglyceride and cholesterol levels. AMPK phosphorylation, an energy sensor for lipid metabolism, was reduced, accompanied by decreased expression of fatty acid oxidation genes and increased expression of lipogenesis genes. Oxidative stress and inhibition of AMPK phosphorylation in HepG2 cells led to cellular lipid accumulation. These findings suggest that AKI induces hepatic lipid accumulation through decreased fatty acid metabolism and increased lipogenesis, with oxidative stress playing a role in downregulating the AMPK signaling pathway.