Dual Roles of Mammalian Target of Rapamycin in Regulating Liver Injury and Tumorigenesis in Autophagy‐Defective Mouse Liver
-
- Hong‐Min Ni
- Department of Pharmacology, Toxicology and Therapeutics,University of Kansas Medical Center,Kansas City,KS
-
- Xiaojuan Chao
- Department of Pharmacology, Toxicology and Therapeutics,University of Kansas Medical Center,Kansas City,KS
-
- Hua Yang
- Department of Pharmacology, Toxicology and Therapeutics,University of Kansas Medical Center,Kansas City,KS
-
- Fengyan Deng
- Department of Pharmacology, Toxicology and Therapeutics,University of Kansas Medical Center,Kansas City,KS
-
- Shaogui Wang
- Department of Pharmacology, Toxicology and Therapeutics,University of Kansas Medical Center,Kansas City,KS
-
- Qingyun Bai
- Department of Pharmacology, Toxicology and Therapeutics,University of Kansas Medical Center,Kansas City,KS
-
- Hui Qian
- Department of Pharmacology, Toxicology and Therapeutics,University of Kansas Medical Center,Kansas City,KS
-
- Yue Cui
- Department of Environmental and Occupational Health Sciences,University of Washington,Seattle,WA
-
- Wei Cui
- Department of Pathology,University of Kansas,Medical Center,Kansas City,KS
-
- Yinghong Shi
- Department of Liver Surgery & Transplantation,Liver Cancer Institute, Zhongshan Hospital, Fudan University,Shanghai,China
-
- Wei‐Xing Zong
- Department of Chemical Biology, Ernest Mario School of Pharmacy,Rutgers University,Piscataway,NJ
-
- Zhengtao Wang
- Institute of Chinese Materia Medica,Shanghai University of Traditional Chinese Medicine,Shanghai,China
-
- Li Yang
- Institute of Chinese Materia Medica,Shanghai University of Traditional Chinese Medicine,Shanghai,China
-
- Wen‐Xing Ding
- Department of Pharmacology, Toxicology and Therapeutics,University of Kansas Medical Center,Kansas City,KS
Description
<jats:p>Autophagy is a lysosomal degradation pathway that degrades cytoplasmic proteins and organelles. Absence of autophagy in hepatocytes has been linked to promoting liver injury and tumorigenesis; however, the mechanisms behind why a lack of autophagy induces these complications are not fully understood. The role of mammalian target of rapamycin (mTOR) in impaired autophagy‐induced liver pathogenesis and tumorigenesis was investigated by using liver‐specific autophagy related 5 knockout (L‐ATG5 KO) mice, L‐ATG5/mTOR, and L‐ATG5/Raptor double knockout (DKO) mice. We found that deletion of mTOR or Raptor in L‐ATG5 KO mice at 2 months of age attenuated hepatomegaly, cell death, and inflammation but not fibrosis. Surprisingly, at 6 months of age, L‐ATG5/mTOR DKO and L‐ATG5/Raptor DKO mice also had increased hepatic inflammation, fibrosis, and liver injury, similar to the L‐ATG5 KO mice. Moreover, more than 50% of L‐ATG5/mTOR DKO and L‐ATG5/Raptor DKO mice already developed spontaneous tumors, but none of the L‐ATG5 KO mice had developed any tumors at 6 months of age. At 9 months of age, all L‐ATG5/mTOR DKO and L‐ATG5/Raptor DKO had developed liver tumors. Mechanistically, L‐ATG5/mTOR DKO and L‐ATG5/Raptor DKO mice had decreased levels of hepatic ubiquitinated proteins and persistent nuclear erythroid 2 p45‐related factor 2 activation but had increased Akt activation compared with L‐ATG5 KO mice. <jats:italic toggle="yes">Conclusion:</jats:italic> Loss of mTOR signaling attenuates the liver pathogenesis in mice with impaired hepatic autophagy but paradoxically promotes tumorigenesis in mice at a relatively young age. Therefore, the balance of mTOR is critical in regulating the liver pathogenesis and tumorigenesis in mice with impaired hepatic autophagy.</jats:p>
Journal
-
- Hepatology
-
Hepatology 70 (6), 2142-2155, 2019-06-24
Ovid Technologies (Wolters Kluwer Health)
- Tweet
Details 詳細情報について
-
- CRID
- 1364233269157511424
-
- ISSN
- 15273350
- 02709139
-
- Data Source
-
- Crossref