Dual Roles of mTOR in Regulating Liver Injury and Tumorigenesis in Autophagy Defective Mouse Liver.

08:00 EDT 16th May 2019 | BioPortfolio

Summary of "Dual Roles of mTOR in Regulating Liver Injury and Tumorigenesis in Autophagy Defective Mouse Liver."

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 is 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 Atg5 knockout (L-Atg5 KO) mice, L-Atg5/mTOR, and L-Atg5/Raptor double knockout (DKO) mice. At two months of age, we found that deletion of mTOR or Raptor in L-Atg5 KO mice attenuated hepatomegaly, cell death and inflammation but not fibrosis. Surprisingly, at six 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 six months of age. At nine 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 deceased levels of hepatic ubiquitinated proteins and persistent Nrf2 activation but had increased Akt activation compared with L-Atg5 KO mice. In conclusion, 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. This article is protected by copyright. All rights reserved.


Journal Details

This article was published in the following journal.

Name: Hepatology (Baltimore, Md.)
ISSN: 1527-3350


DeepDyve research library

PubMed Articles [17568 Associated PubMed Articles listed on BioPortfolio]

TIGAR alleviates ischemia/reperfusion-induced autophagy and ischemic brain injury.

Autophagy has been reported to play protective and pathogenetic roles in cerebral ischemia/reperfusion (I/R)-induced neuronal injury. Our previous studies have shown that TP53-induced glycolysis and a...

Augmenter of liver regeneration protects against ethanol-induced acute liver injury by promoting autophagy.

Alcoholic liver disease is associated with high morbidity and mortality, and treatment options are limited to date. Augmenter of liver regeneration (ALR) may protect against hepatic injury caused by c...

Impaired Endothelial Autophagy Promotes Liver Fibrosis By Aggravating The Oxidative Stress Response During Acute Liver Injury.

Endothelial dysfunction plays an essential role in initiation and progression of liver injury, yet phenotypic regulation of liver endothelial cells remains unknown. Autophagy is an endogenous protecti...

The PI3K/Akt/mTOR signaling pathway plays a role in regulating aconitine-induced autophagy in mouse liver.

Aconitine, a major aconitum alkaloid, is well known for its high toxicity that induces severe arrhythmias and neurological symptoms. One mechanism of aconitine-induced toxic responses is the induction...

The Dual Role of HIV-1 gp120 V3 Loop-Induced Autophagy in the Survival and Apoptosis of the Primary Rat Hippocampal Neurons.

HIV-1 gp120, an important subunit of the envelope spikes that decorate the surface of virions, is known to play a vital role in neuronal injury during HIV-1-associated neurocognitive disorder (HAND), ...

Clinical Trials [7374 Associated Clinical Trials listed on BioPortfolio]

Autophagy and Pathological Aging

Autophagy is recognized as a central mechanism for the regulation of aging. . Osteoporosis (OA) and Alzheimer's disease (AD) are two forms of pathological aging, sometimes entangled, inclu...

A Double-Blind, Placebo-Controlled Trial of Anti-Aging, Pro-Autophagy Effects of Metformin in Adults With Prediabetes

The goal of this pilot and feasibility study is to investigate the effects of a short course of metformin therapy on a surrogate marker of cellular senescence and autophagy among adult pat...

Ethanol Induces Skeletal Muscle Autophagy

In this study we plan to demonstrate that ethanol induces skeletal muscle autophagy to degrade MAA adducts.

Phase I Study of Palomid 529 a Dual TORC1/2 Inhibitor of the PI3K/Akt/mTOR Pathway for Advanced Neovascular Age-Related Macular Degeneration

Palomid 529 is a dual TORC1/2 inhibitor of the PI3K/Akt/mTOR pathway having broad activity in angiogenesis and cellular proliferation. Palomid 529 will be examined to determine if the saf...

Correlation Between Autophagy-related Proteins and Inflammatory Markers in Hemodialysis Patients

One recent study demonstrated impaired autophagy in patients receiving hemodialysis (HD). To clarify whether this alteration is related to the inflammatory state in HD patients, we focused...

Medical and Biotech [MESH] Definitions

An adaptor protein, consisting of seven WD REPEATS along its length, that functions as a component of the MECHANISTIC TARGET OF RAPAMYCIN COMPLEX 1 and MTORC2 COMPLEX. It interacts directly with MTOR to enhance its kinase activity and stabilizes the MTOR-RPTOR PROTEIN interaction in nutrient-poor conditions, favoring RPTOR inhibition of MTOR activity.

A secreted angiopoietin-like protein expressed under hypoxic conditions by ENDOTHELIAL CELLS. It inhibits cell proliferation, cell migration, and tubule formation; the inactive form accumulates in the endothelial EXTRACELLULAR MATRIX, reducing vascular leakage. ANGPTL4 has direct roles in regulating glucose and lipid metabolism, as well as INSULIN SENSITIVITY, and may also function as a regulator of angiogenesis and tumorigenesis.

Sudden liver failure in the presence of underlying compensated chronic LIVER DISEASE (e.g., LIVER CIRRHOSIS; HEPATITIS; and liver injury and failure) due to a precipitating acute hepatic insult.

A spectrum of clinical liver diseases ranging from mild biochemical abnormalities to ACUTE LIVER FAILURE, caused by drugs, drug metabolites, and chemicals from the environment.

A spectrum of clinical liver diseases ranging from mild biochemical abnormalities to ACUTE LIVER FAILURE, caused by drugs, drug metabolites, herbal and dietary supplements and chemicals from the environment.

Quick Search


DeepDyve research library

Relevant Topic

Hepatology is the study of liver, gallbladder, biliary tree, and pancreas, and diseases associated with them. This includes viral hepatitis, alcohol damage, cirrhosis and cancer. As modern lifestyles change, with alcoholism and cancer becoming more promi...

Searches Linking to this Article