Long-term effects of low-dose mouse liver irradiation involve ultrastructural and biochemical changes in hepatocytes that depend on lipid metabolism

Abstract

The aim of the study was to investigate long-term effects of radiation on the (ultra)structure and function of the liver in mice. The experiments were conducted on wild-type C57BL/6J and apolipoprotein E knock-out (ApoE) male mice which received a single dose (2 or 8 Gy) of X-rays to the heart with simultaneous exposure of liver to low doses (no more than 30 and 120 mGy, respectively). Livers were collected for analysis 60 weeks after irradiation and used for morphological, ultrastructural, and biochemical studies. The results show increased damage to mitochondrial ultrastructure and lipid deposition in hepatocytes of irradiated animals as compared to non-irradiated controls. Stronger radiation-related effects were noted in ApoE mice than wild-type animals. In contrast, radiation-related changes in the activity of lysosomal hydrolases, including acid phosphatase, β-glucuronidase, N-acetyl-β-D-hexosaminidase, β-galactosidase, and α-glucosidase, were observed in wild type but not in ApoE-deficient mice, which together with ultrastructural picture suggests a higher activity of autophagy in ApoE-proficient animals. Irradiation caused a reduction of plasma markers of liver damage in wild-type mice, while an increased level of hepatic lipase was observed in plasma of ApoE-deficient mice, which collectively indicates a higher resistance of hepatocytes from ApoE-proficient animals to radiation-mediated damage. In conclusion, liver dysfunctions were observed as late effects of irradiation with an apparent association with malfunction of lipid metabolism.

Aging-Related Changes in the Ultrastructure of Hepatocytes and Cardiomyocytes of Elderly Mice Are Enhanced in ApoE-Deficient Animals

“…Aging processes are accelerated by many factors such as smoking, ultraviolet light, and other environmental factors [22][23][24]. Additionally, obesity, atherosclerosis, and dyslipidemia produce a variety of alterations that may cause changes in both liver and cardiac morphology which predispose to organ dysfunction [8,25].…”

Microarray analysis identifies coding and non-coding RNA markers of liver injury in whole body irradiated mice

“…Prior literature has shown that radiation induces increased triglyceride storage, lipid metabolism dysfunction, and mitochondrial dysfunction in the liver 10 , 95 , 96 . These studies led us to interrogate the impact of radiation on lipid metabolism in our mouse model.…”

Radiation-induced liver injury and hepatocyte senescence

“…Glucose and lipid metabolism disorders are observed even after low-dose radiation, and the effects will last a long time. Additionally, livers suffering from lipid metabolism disorder are more sensitive to RILI [ 43 ]. Attention needs to be paid to basic liver conditions when receiving abdominal radiotherapy or radiation exposure.…”

“…In addition, they found late peroxisome proliferation-activated receptor (PPAR)α-mediated metabolic alterations and late increases in the levels of cytochrome P450 (CYP450) enzymes. In mice that received low-dose radiation, damage to the mitochondrial ultrastructure and lipid deposition in hepatocytes increased compared with the nonirradiated controls, and much more severe RILI was identified in ApoE −/− mice [ 43 ], indicating RILI has an apparent association with lipid metabolism disorder.…”