Functions of autophagy in normal and diseased liver

Czaja, Mark J.; Ding, Wen; Donohue, Terrence M.; Friedman, Scott L.; Kim, Jae Sung; Komatsu, Masaaki; Lemasters, John J.; Lemoine, Antoinette; Lin, Jiandie D.; Ou, Jing-Hsiung; Perlmutter, David H.; Randall, Glenn; Ray, Ratna B.; Tsung, Allan; Yin, Xiao Ming

doi:10.4161/auto.25063

Cited by 407 publications

(412 citation statements)

References 329 publications

(460 reference statements)

Supporting

Mentioning

402

Contrasting

Unclassified

Order By: Relevance

“…While autophagy helps to prevents tumorigenesis, it is also used by the cancer cells for survival against apoptosis by traditional chemotherapeutic drugs [303,304] . Initially, autophagy functions are as a tumor suppressor and later, when HCC has developed, the autophagy may contribute to its growth [303,305] . Microbes have evolved mechanisms to evade and exploit autophagy and both HBV and HCV use autophagy for their own survival [306] .…”

Section: Resultsmentioning

confidence: 99%

Hepatocellular carcinoma and the risk of occupational exposure

Rapisarda

Loreto

Malaguarnera

et al. 2016

WJH

View full text Add to dashboard Cite

Hepatocellular carcinoma (HCC) is the most common type of liver cancer. The main risk factors for HCC are alcoholism, hepatitis B virus, hepatitis C virus, nonalcoholic steatohepatitis, obesity, type 2 diabetes, cirrhosis, aflatoxin, hemochromatosis, Wilson's disease and hemophilia. Occupational exposure to chemicals is another risk factor for HCC. Often the relationship between occupational risk and HCC is unclear and the reports are fragmented and inconsistent. This review aims to summarize the current knowledge regarding the association of infective and non-infective occupational risk exposure and HCC in order to encourage further research and draw attention to this global occupational public health problem. Core tip: Hepatocellular carcinoma (HCC) is the fifth most common human cancer. This review summarizes current knowledge regarding the occupational risk factors of HCC. In particular, we underline not only the infective but also non-infective occupational risk exposure, including chemical agents and toxic metabolites which are a major cause of liver damage.

show abstract

Section: Resultsmentioning

confidence: 99%

Hepatocellular carcinoma and the risk of occupational exposure

Rapisarda

Loreto

Malaguarnera

et al. 2016

WJH

View full text Add to dashboard Cite

show abstract

“…26 It is noteworthy that obesity and hepatic steatosis, diseases closely associated with mitochondrial and autophagic dysfunction, 27 are mechanistically linked to hyperacetylation of mitochondrial proteins. 28,29 Here we provide evidence that removing acetyl group of MFN2 by SIRT1 plays a pivotal role in hepatocyte autophagy and survival after I/R injury.…”

Section: Discussionmentioning

confidence: 99%

Sirtuin 1 suppresses mitochondrial dysfunction of ischemic mouse livers in a mitofusin 2-dependent manner

et al. 2015

View full text Add to dashboard Cite

Ischemia/reperfusion (I/R) injury is a major cause of morbidity and mortality after liver surgery. The role of Sirtuin 1 (SIRT1) in hepatic I/R injury remains elusive. Using human and mouse livers, we investigated the effects of I/R on hepatocellular SIRT1. SIRT1 expression was significantly decreased after I/R. Genetic overexpression or pharmacological activation of SIRT1 markedly suppressed defective autophagy, onset of the mitochondrial permeability transition, and hepatocyte death after I/R, whereas SIRT1-null hepatocytes exhibited increased sensitivity to I/R injury. Biochemical approaches revealed that SIRT1 interacts with mitofusin-2 (MFN2). Furthermore, MFN2, but not MFN1, was deacetylated by SIRT1. Moreover, SIRT1 overexpression substantially increased autophagy in wild-type cells, but not in MFN2-deficient cells. Thus, our results demonstrate that the loss of SIRT1 causes a sequential chain of defective autophagy, mitochondrial dysfunction, and hepatocyte death after I/R. Cell Death and Differentiation (2016) 23, 279-290; doi:10.1038/cdd.2015; published online 17 July 2015During hepatic resection and liver transplantation operations, inflow occlusion is employed to temporarily limit blood flow to minimize intraoperative blood loss. Although prolonged ischemia eventually causes tissue injury, severe damage paradoxically does not occur until recovery of blood flow and restitutions of normal physiological pH.1 Ischemia/reperfusion (I/R) injury is a key cause of postoperative liver failure during hemorrhagic shock, hepatectomy, and liver transplantation. Despite continuous efforts, substantial benefits from current strategies have not been realized, mainly because of the multifactorial nature of I/R injury.I/R initiates opening of high-conductance permeability transition pores in the mitochondrial inner membranes, leading to mitochondrial permeability transition (MPT).2 Onset of the MPT uncouples oxidative phosphorylation and depolarizes mitochondrial membrane potential (ΔΨ m ) that in turn causes ATP depletion and cell death.Autophagy is an evolutionarily conserved catabolic process. Among the three forms of autophagy, macroautophagy is of particular importance in the liver, as it not only degrades unneeded intracellular proteins but also digests injured or dysfunctional organelles such as abnormal mitochondria. 3 We have shown that impaired autophagy contributes to liver I/R injury. [4][5][6] Sirtuin1 (SIRT1) deacetylates Lys residues of both histone and nonhistone targets, and is activated in response to fasting and calorie restriction in the liver, a condition inducing autophagy. 7,8 Despite its extramitochondrial localization, SIRT1 appears to affect mitochondrial biogenesis 9 and bioenergetics, 10 but its mechanisms remain elusive. Using isolated hepatocytes, mouse livers, SIRT1-null mice, and human livers, we here demonstrate that I/R depletes livers of SIRT1 and that specific overexpression of SIRT1 mitigates defective autophagy, onset of the MPT, and subsequent hepatocyte death after both in vitro...

show abstract

“…46 Although autophagy is generally thought to be a cell survival pathway against various adverse stresses, 9,46 it has been reported that a general caspase inhibitor ZVAD induced autophagic cell death in a cell culture model. 47 However, a later study found that ZVAD did not induce autophagy but instead blocked autophagosome maturation and induced necrosis.…”

Section: Discussionmentioning

confidence: 99%

“…6e8 Autophagy is a catabolic lysosomal degradation pathway, which plays a critical role in normal liver physiology and liver diseases. 9 Autophagy involves the formation of doublemembrane autophagosomes that engulf intracellular proteins and organelles and then fuse with lysosomes to form autolysosomes, where enveloped cargo is degraded. Although under certain specific conditions autophagy may contribute to cell death, 10 the liver basal autophagy seems to act as a cell survival function and is critical to maintain liver homeostasis.…”

mentioning

confidence: 99%

Caspase Inhibition Prevents Tumor Necrosis Factor-α–Induced Apoptosis and Promotes Necrotic Cell Death in Mouse Hepatocytes in Vivo and in Vitro

McGill

Chao

et al. 2016

The American Journal of Pathology

Self Cite

View full text Add to dashboard Cite

How different cell death modes and cell survival pathways cross talk remains elusive. We determined the interrelation of apoptosis, necrosis, and autophagy in tumor necrosis factor (TNF)-a/actinomycin D (ActD) and lipopolysaccharide/D-galactosamine (GalN)-induced hepatotoxicity in vitro and in vivo. We found that TNF-a/ActD-induced apoptosis was completely blocked by a general caspase inhibitor ZVADfmk at 24 hours but hepatocytes still died by necrosis at 48 hours. Inhibition of caspases also protected mice against lipopolysaccharide/GalN-induced apoptosis and liver injury at the early time point, but this protection was diminished after prolonged treatment by switching apoptosis to necrosis. Inhibition of receptor-interacting protein kinase (RIP)1 by necrostatin 1 partially inhibited TNF-a/ZVAD-induced necrosis in primary hepatocytes. Pharmacologic inhibition of autophagy or genetic deletion of Atg5 in hepatocytes did not protect against TNF-a/ActD/ZVAD-induced necrosis. Moreover, pharmacologic inhibition of RIP1 or genetic deletion of RIP3 failed to protect and even exacerbated liver injury after mice were treated with lipopolysaccharide/GalN and a pan-caspase inhibitor. In conclusion, our results suggest that different cell death mode and cell survival pathways are closely integrated during TNF-ae induced liver injury when both caspases and NF-kB are blocked. Moreover, results from our study also raised concerns about the safety of currently ongoing clinical trials that use caspase inhibitors. (Am J Pathol 2016 http://dx

show abstract

Functions of autophagy in normal and diseased liver

Cited by 407 publications

References 329 publications

Hepatocellular carcinoma and the risk of occupational exposure

Hepatocellular carcinoma and the risk of occupational exposure

Sirtuin 1 suppresses mitochondrial dysfunction of ischemic mouse livers in a mitofusin 2-dependent manner

Caspase Inhibition Prevents Tumor Necrosis Factor-α–Induced Apoptosis and Promotes Necrotic Cell Death in Mouse Hepatocytes in Vivo and in Vitro

Contact Info

Product

Resources

About