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. 2019 Jan 13;20(2):300. doi: 10.3390/ijms20020300

Table 2.

Summary of autophagy in liver injury.

Experimental Model Characteristics of Autophagy Function of Autophagy References
Rat liver
(Intraperitoneal injection of DMNA)

  1. Electron micrograph of autophagic vacuoles

  2. Increased autophagic vacuoles when the onset of necrosis is detected

  1. Degradation of organelles by autophagic vacuoles in DMNA-treated liver cells

  2. Associated with the occurrence of hepatocellular necrosis

 [272]
Mouse liver
(Intravenous injection of lysine acetylsalicylate		 Electron micrograph of single- and multiple-membranous autophagic vacuoles The engulfment of intracellular components within autophagic vacuoles that may protect the lysine acetylsalicylate-treated liver cells against injury [279]
Rat liver
(Stressors: fasting, cortisol injection, reserpine injection, restraint, spinal cord transection, etc.) 		Electron micrograph of single- and multiple-membranous autophagic vacuoles Protection of liver cells against multiple stress responses [364]
Rat liver
(Lethal Escherichia coli)		 Electron micrograph of autophagic vacuoles Association of hepatic autophagy in Escherichia coli-induced liver injury [365]
Rat hepatocytes
(Calcium ionophore, microtubule active agents, and hepatotoxins)		 Detection of autophagic degradation of endogenous proteins Decreased autophagic degradation by liver injury [366]

  1. Liver specimens of normal and α1-AT-deficeint patients

  2. Wild type and PiZ (α1-AT-deficeint) mice

  1. Electron micrograph of autophagic vacuoles that engulf mitochondria

  2. Colocalization of α1-AT and cathepsin D in fasted mouse liver

  3. Enhanced the formation of autophagic vacuoles in hepatocytes of fasting mouse liver

  4. Sequestration of ER-retained and mutated α1-ATZ aggregated protein by autophagic vacuoles

  1. Induced mitochondrial injury and mitochondrial autophagy in α1-AT-deficient livers

  2. Suppressed autophagy activation of deficiency of α1-AT in liver

  3. Autophagic elimination of α1-ATZ aggregated protein

  4. Reduced the inclusion bodies of α1-ATZ aggregated protein and liver injury by rapamycin-induced hepatic autophagy

 [353,354,355,371,372,373]

  1. Wild type and liver-specific knockout of ATG7 mice

  2. Hepatocellular carcinoma cell lines

  1. Impaired autophagy by ATG7-deficicent mice by electron microscopy analysis and detection of LC3 lipidation

  2. Degradation of p62/SQSTM1 by autophagy

  1. Induced hepatomegaly and the swelling of hepatic cells deficient of ATG7

  2. Accumulated peroxisomes and deformed mitochondria in the liver cells of ATG7-deficient mice

  3. Accumulated ubiquitin- and p62/SQSTM1 containing inclusion bodies in the liver cells of ATG7-deficient mice

  4. Suppression of liver dysfunction in ATG7-deficient mice by additional knockout of p62/SQSTM1

  5. Formation of p62/SQSTM1- and Keap1-postivie inclusion bodies in ATG7-deficient hepatocytes

  6. Induction of Nrf2-dependent transcriptions of antioxidant genes in ATG7-deficient livers by p62/SQSTM1-Keap1 interaction

  7. Amelioration of liver dysfunction in ATG7-deficient livers by additional ablation of Nrf2

  8. Exacerbation of liver injury in ATG7-deficient livers by additional knockout of Nrf2

  9. Induction of hepatocellular carcinoma in the mice livers loss of ATG7 through activation of Nrf2

 [356,377,378,379,380,381]
Liver specimens of liver-related diseases patients

  1. Electron micrograph of autophagic vacuoles in liver after ischemia and reperfusion

  2. Enhanced lipidation of ATG8/LC3

  3. Increased of the formation of autophagic vacuoles in the ischemia and reperfusion-injured liver with ischemic preconditioning

 Association of increased autophagy with the chemotherapy-injured liver after ischemic preconditioning [382,383]
Mouse hepatocytes
(In vivo and in vitro ischemia and reperfusion)

  1. Detection of the lipidation of ATG8/LC3

  2. Analysis of autophagic flux by fluorescence signal of AdmCherry-GFP-LC3

  3. Detections of the processing and expression of cathepsin D

 Amelioration of liver damage and restoration of mitochondrial function in liver after ischemia and reperfusion [307]

  1. Wild type and GFP-LC3-transgenic mice

  2. Isolated primary mouse hepatocytes

  1. Detection of lipidation of ATG8/LC3 and p62/SQSTM1 degradation

  2. Electron micrograph of autophagic vacuoles that engulf mitochondria

  3. The expression of GFP-LC3-labeled punctate structure

  1. Induction of autophagy in livers of ethanol-treated mice

  2. Enhanced cell apoptosis of hepatocytes and liver injury by inhibition of autophagy

  3. Activation of mitophagy to modulate ethanol-induced liver steatosis

 [345,384]
Primary mouse hepatocytes
(LPS; Cecal ligation and performation)

  1. Electron micrograph of autophagic vacuoles

  2. Detection of lipidation of ATG8/LC3

  3. Immunofluorescence analysis of ATG8/LC3

  1. Induction of hepatic autophagy through HO-1 upregulation in the hepatocytes treated with LPS and cecal ligation of performation

  2. Enhanced cell apoptosis in in the hepatocytes treated with LPS and cecal ligation of performation by interfered with autophagy

 [385]

  1. Human hepatoma, HepG2 cells

  2. Mouse liver

  1. Electron micrograph of autophagic vacuoles

  2. Detection of lipidation of ATG8/LC3

  3. Immunofluorescence analysis of GFP-LC3-labeled punctate structure

 Protection of fatty acids-induced lipotoxicity and liver injury by autophagy [386]
Chang liver cells
(PEI treatment)

  1. Electron micrograph of autophagic vacuoles

  2. Immunofluorescence analysis of ATG8/LC3

 Enhancement of the PEI-induced cytotoxicity in liver cells by autophagy [387]
Wild type and liver-specific knockout of ATG7 mice
(APAP treatment)

  1. Electron micrograph of autophagic vacuoles

  2. Detection of lipidation of ATG8/LC3

  1. Induction of hepatic autophagy by APAP treatment

  2. Induced cell apoptosis and liver injury in the ATG7-deficient mouse livers treated with APAP

  3. Enhanced mitochondrial damage, ROS production, and depolarization of mitochondria in the ATG7-deficient mouse livers treated with APAP

 [388]
Rat liver
(Cold ischemia/warm reperfusion; liver transplantation)

  1. Electron micrograph of autophagic vacuoles

  2. Immunofluorescence analysis of ATG8/LC3

  1. Association of hepatic autophagy with cold ischemia/warm reperfusion-induced cell death of liver injury

  2. Suppressed liver injury by inhibition of autophagy

  3. Participation of autophagy in the cell death of dysfunctional liver graft

 [389]
Liver specimens of patients Electron micrograph of autophagic vacuoles Promotion of cell death in anorexia nervosa livers of patients by starvation-induced autophagy [301]

  1. Wild type and IGF-1 deficient mice

  2. Human hepatoma, HepG2 cells

 Immunofluorescence analysis of GFP-LC3-labeled punctate structure

  1. Suppressed autophagy in senescent livers

  2. Rescued hepatic autophagy by loss of IGF-1

  3. Amelioration of ageing-induced liver injury by IGF-1 deficiency-induced autophagy activation

 [390]

  1. Wild type and PiZ (α1-AT-deficeint) mice

  2. Wild type and ATG7−/− MEF

  1. Detections of lipidation of ATG8/LC3 and p62/SQSTM1 degradation

  2. Immunofluorescence analysis of GFP-LC3-labeled punctate structure

  3. Electron micrograph of autophagic vacuoles that eliminates α1-ATZ inclusion bodies

  1. Enhanced autophagic flux by liver-directed gene transfer of TFEB

  2. Increased autophagic degradation of mutated α1-ATZ polymer by liver-directed gene transfer of TFEB

  3. Decreased the α1-ATZ-induced liver injury by TFEB-enhanced autophagy

 [391]
Isolated hepatocytes from wild type and caspase 1−/− mice

  1. Immunofluorescence analysis of GFP-LC3-labeled punctate structure

  2. Detection of lipidation of ATG8/LC3

  1. Decreased autophagic flux in caspase 1−/− hepatocytes after hypoxia/reoxygenation

  2. Activation of autophagy through caspase 1-dependent upregulation of Beclin 1

  3. Selective elimination of mitochondria by caspase 1-mediated autophagy activation

  4. Reduced liver injury and oxidative stress after hypoxia/reoxygenation by caspase 1-mediated autophagy

 [392]
Isolated mouse hepatocytes and Kupffer cells Detection of lipidation of ATG8/LC3

  1. Enhanced the activation of NLRP3 inflammasome after LPS challenge by deficiency of Kir6.2/K-ATP channel

  2. Aggravated ER stress and autophagy in the Kir6.2-deficicency-induced NLRP3 inflammasome activation

 [393]
Mouse liver Detections of lipidation of ATG8/LC3 and p62/SQSTM1 degradation

  1. Induction of APAP-induced hepatic necrosis by protein kinase C

  2. Suppressed APAP-induced hepatic cytotoxicity by PKC inhibitors

  3. Repressed APAP-induced hepatic cytotoxicity by activated autophagy

 [394]
Isolated mouse hepatic stellate cells Detections of lipidation of ATG8/LC3 and p62/SQSTM1 degradation

  1. Decreased hepatic stellate cell activation and autophagy by blocking of inositol-requiring enzyme 1 (IRE1α)

  2. Induced the oxidative stress and Nrf2-dependent antioxidant response by IRE1α blocking-repressed autophagy

 [395]
Rat liver
(Ischemia/reperfusion)		 Detections of lipidation of ATG8/LC3

  1. Alleviated ischemia/reperfusion-induced liver injury by tunicamycin-preconditioning ER stress

  2. The repressed ischemia/reperfusion-induced liver injury by IRE1 and glucose-regulated protein 78

  3. Prevented live apoptosis after ischemia/reperfusion by activated autophagy

 [396]
Mouse liver
(LPS/D-galactosamine (GalN))		 Detections of lipidation of ATG8/LC3 Induced ER stress and autophagy at the early stage of LPS/GalN-induced liver injury [397]
Mouse liver
(Ischemia/reperfusion; fasting)		 Detections of lipidation of ATG8/LC3

  1. Protection of hepatic injury after ischemia/reperfusion by one-day fasting

  2. Reduced circulating HMGB1 and cytoplasmic translocation of HMGB1 and activated autophagy in liver injury by fasting

  3. Suppressed protection of liver injury by inhibition of autophagy

  4. Prevented HMGB1 translocation and elevated circulating HMGB1 by Sirt1 inhibition

 [398]
Wild type and liver-specific knockout of ATG7 mice Detections of lipidation of ATG8/LC3 and p62/SQSTM1 degradation

  1. Induced HMGB1 release from hepatocytes by loss of autophagy

  2. Promoted ductular reaction by HMGB1 in autophagy-deficient livers

  3. Prevented ductular reaction by inhibition of HMGB1

  4. HMGB1 and receptor for advanced glycation end product promote tumorigenesis in autophagy-deficient livers

 [399]
Mouse liver
(Ischemia/reperfusion; fasting)		 Detections of lipidation of ATG8/LC3 and p62/SQSTM1 degradation

  1. Protection of acute liver failure by PPARα-activated autophagy

  2. Attenuated inflammatory response by PPARα-activated autophagy

 [349]
Wild type and NRBF2 knockout mice

  1. Detections of lipidation of ATG8/LC3 and p62/SQSTM1 degradation

  2. Immunofluorescence analysis of mcherry-GFP-LC3B

  1. Association of NRBF2 with PI(3)K complex, which is required for autophagy initiation

  2. Impaired autophagic degradation by NRBF2 knockdown

  3. Induced hepatic necrosis in NRBF2-deficient mice

  4. Prevented ER stress-mediated cytotoxicity and liver injury by NRBF2-modulated autophagy

 [400]
Mouse liver
(Cecal ligation and puncture)		 Immunofluorescence analysis of ATG8/LC3

  1. Limited sepsis-induced liver injury by AMPK activation

  2. Decrease cytokine induction by AMPK activation

  3. Increased liver injury by repressed AMPK-inhibited autophagy

  4. Attenuated mitochondrial dysfunction by AMPK-mediated autophagy

  5. Suppressed inflammasome and apoptosis and protection against fulminant hepatitis by AMPK-mediated autophagy

 [401,402,403]
Wild type and liver specific HIF-1β knockout mice

  1. Detection of lipidation of ATG8/LC3

  2. Immunofluorescence analysis of GFP-LC3

  3. Electron micrograph of autophagic vacuoles

  1. Increased BNIP3 and BNIP3L expressions by HIF-1β in liver cells after acute ethanol treatment

  2. Limited liver injury and steatosis by deficiency of HIF-1β

  3. Protection of liver injury by FoxO3-activated autophagy in HIF-1β-knockout hepatocytes

 [404]
Mouse liver
(Ischemia/reperfusion)		 Detections of lipidation of ATG8/LC3 and p62/SQSTM1 degradation

  1. Amelioration of liver injury after ischemia/reperfusion by ATRA

  2. Reduced hepatic apoptosis and inflammation after ischemia/reperfusion by ATRA

  3. Promoted autophagy through Foxo3a/phosphor-Akt/Foxo1 pathway by ATRA

 [405]
Mouse liver
(Ischemia/reperfusion)

  1. Detection of lipidation of ATG8/LC3

  2. Immunofluorescence analysis of ATG8/LC3

  1. Impaired autophagy through HO-1/calpain 2-signaling in liver steatosis

  2. Increased sensitivity of liver injury after ischemia/reperfusion by impaired autophagy

 [406]
Mouse liver
(Ischemia/reperfusion)

  1. Detections of lipidation of ATG8/LC3 and p62/SQSTM1 degradation

  2. Electron micrograph of autophagic vacuoles

  3. Immunofluorescence analysis of ATG8/LC3

  1. Protection of liver injury after ischemia/reperfusion by 1-2-cyano3-,12-dioxooleana-1,9(11)-dien-28-oyl-imidazole-mediated autophagy activation

  2. Protection of mitochondrial dysfunction and excessive ROS during liver injury after ischemia/reperfusion

  3. Reduced liver inflammation and apoptosis after ischemia/reperfusion by CDDC-Im-enhanced autophagy

  4. Involvement of Nrf2/HO-1 pathway in the autophagy-mediated protection of liver injury after ischemia/reperfusion

 [407]
Mouse liver
(LPS/D-GalN)

  1. Detections of lipidation of ATG8/LC3 and p62/SQSTM1 degradation

  2. Immunofluorescence analysis of mRFP-GFP-LC3

  1. Attenuated LPS/D-GalN- and ConA-induced acute liver failure by FK866

  2. Amelioration of acute liver failure through FK866-induced autophagy

  3. Reduced liver injury by rapamycin-induced autophagy

  4. Activation of FK866-induced autophagy through suppressed JNK signaling

  5. Alleviated hepatotoxicity by FK866-increased autophagy

 [408]
Wild type and Cd38−/− mice
(LPS/D-GalN)

  1. Detections of lipidation of ATG8/LC3 and p62/SQSTM1 degradation

  2. Immunofluorescence analysis of mCherry-GFP-LC3

  3. Electron micrograph of autophagic vacuoles

  1. Impaired autophagy in Cd38−/− hepatocytes after LPS/D-GallN-induced liver injury

  2. Protection of LPS/D-GalN-induced liver injury by CD38

  3. Promoted autophagy by NAADP in the protection of LPS/D-GalN-induced liver injury by CD38

 [409]
Wild type and liver specific KLF6 knockout mice

  1. Detections of lipidation of ATG8/LC3 and p62/SQSTM1 degradation

  2. Electron micrograph of autophagic vacuoles

  3. Immunofluorescence analysis of mRFP-GFP-LC3

  1. Induced KLF6 by acute human liver injury

  2. Attenuated liver regeneration and autophagy activation by KLF6 in liver after partial hepatectomy

  3. Induced autophagy by KLF6 through the binding to promoter regions of Beclin 1 and ATG7

 [410]