| First Author | Wang Y | Year | 2019 |
| Journal | Mol Med Rep | Volume | 20 |
| Issue | 4 | Pages | 3224-3232 |
| PubMed ID | 31432115 | Mgi Jnum | J:289936 |
| Mgi Id | MGI:6435226 | Doi | 10.3892/mmr.2019.10549 |
| Citation | Wang Y, et al. (2019) Hepatic NPC1L1 overexpression attenuates alcoholic autophagy in mice. Mol Med Rep 20(4):3224-3232 |
| abstractText | Alcohol consumption causes liver steatosis in humans. Metabolic disorders of lipids are one of the factors that cause liver steatosis in hepatocytes. Hepatic NiemannPick C1like 1 (NPC1L1) regulates lipid homeostasis in mammals. The relationship between NPC1L1 and autophagy in those with a history of alcohol abuse is unclear. The present study aimed to investigate the function of NPC1L1 in the activation of hepatic autophagy in a mouse model with a human (h)NPC1L1 transgene under alcohol feeding conditions. The mice expressing hNPC1L1 (AdL1) or controls (Adnull) were created by retroorbital adenovirus injection. The AdL1 and Adnull mice were fed with alcohol or a nonalcoholic diet to mimic chronic alcohol consumption in humans. Hepatic autophagy was demonstrated in isolated primary hepatocytes by monitoring autophagic vacuoles under fluorescence microscopy, and by western blotting for autophagic makers. Isolated hepatocytes from the livers of AdL1 mice were treated with different doses of ezetimibe to study the restoration of autophagy. Chronic alcohol feeding caused liver injury and steatosis, shown by significantly higher levels of plasma alanine transaminase and aspartate transaminase activity, and by hematoxylin and eosin staining in AdL1 and Adnull mice. Compared to Adnull control mice, the microtubuleassociated proteins 1A/1B light chain 3 (LC3) particles in the isolated hepatocytes of AdL1 mice were decreased, both under alcohol and nonalcoholic feeding. The ratio of LC3II/LC3I was significantly decreased, and the level of p62/sequestosome1 protein was significantly increased in AdL1 mice compared with Adnull mice after alcohol feeding. Levels of LC3II protein were statistically increased in hepatocytes isolated from AdL1 mice with ezetimibe treatment. The increase in LC3II expression was dose dependent. Within the tested range, it reached its highest level at 40 microM. The livers of AdL1 mice represent a more humanlike state for the study of hepatic autophagy. Hepatic expression of human NPC1L1 resulted in an inhibition of autophagy; it may contribute to alcoholic fatty liver disease in humans. |
