Abstract
The liver is a major organ in lipid metabolism, and its malfunction leads to various diseases. Nonalcoholic fatty liver disease, the most common chronic liver disorder in developed countries, is characterized by the abnormal retention of excess lipid within hepatocytes and predisposes individuals to liver cancer. We previously reported that the levels of Lissencephaly 1 (LIS1, also known as PAFAH1B1) are down-regulated in human hepatocellular carcinoma. Following up on this observation, we found that genetic deletion of Lis1 in the mouse liver increases lipid accumulation and inflammation in this organ. Further analysis revealed that loss of Lis1 triggers endoplasmic reticulum (ER) stress and reduces triglyceride secretion. Attenuation of ER stress by addition of tauroursodeoxycholic acid (TUDCA) diminished lipid accumulation in the Lis1-deficient hepatocytes. Moreover, the Golgi stacks were disorganized in Lis1-deficient liver cells. Of note, the Lis1 liver-knockout mice exhibited increased hepatocyte ploidy and accelerated development of liver cancer after exposure to the liver carcinogen diethylnitrosamine (DEN). Taken together, these findings suggest that reduced Lis1 levels can spur the development of liver diseases from steatosis to liver cancer and provide a useful model for delineating the molecular pathways that lead to these diseases.
Highlights
The liver is a major organ in lipid metabolism, and its malfunction leads to various diseases
These results indicate that there is no compensatory proliferation of Lis1expressing hepatocytes to regenerate Lis1-deficient liver
When liver sections from these mutant mice were stained for neutral lipids using Oil Red O staining, there was a significant increase in the amount of lipids in Lis1 KO mice compared with the controls, demonstrating a defect in lipid metabolism (Fig. 1C)
Summary
Selective inactivation of Lis in the liver leads to accumulation of lipids in hepatocytes. We found that the activation of insulindependent phosphorylation of AKT was attenuated as a result of Lis depletion in isolated primary hepatocytes in response to insulin (Fig. 2J) These data indicate that Lis KO mice had reduced VLDL–TG secretion and aberrant glucose metabolism, which contribute to the development of fatty liver. Analysis of mRNA from livers of Lis KO mice revealed two times increase in macrophage markers indicated by the expression of macrophage inflammation protein F4/80 (Fig. 3C). Els, one of ER stress response genes, were unchanged in Western blot assay (Fig. 4A), immunohistochemistry staining showed increased HSPA5 expression in about 10% hepatocytes of Lis KO livers (Fig. 4B). Together, these findings indicate that deletion of Lis in mouse liver results in elevated ER stress and hepatic steatosis. These results demonstrated that Lis plays a critical role in hepatocyte ploidy regulation
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