Autophagy in liver diseases

Table 1 Overview of autophagy abnormalities in liver disease

Disease	Abnormalities of autophagy	Results	Ref.
Obesity	↓Autophagy; Hepatocytes: ↓Mitophagy, ↓Lipophagy; HSCs: ↓Autophagy	↑ER stress, →↑Lipids, ↑Insuline resistance, → Anti-fibrotic	Liu et al[203], Lavallard et al[204], Gual et al[205], Tremblay et al[206]
NAFLD	↓Lipophagy; ↓CMA	Lipotoxicity, ↑Lipogenic enzymes	Madrigal-Matute et al[30], Zhou et al[234], Niso-Santano et al[235], Singh et al[236]
NASH	Hepatocytes: ↓Autophagy, ↓Mitophagy; Kupffer cells: ↓Autophagy; LSECs: ↓Autophagy	↑Mallory-Denk bodies, ↑Inflammasome activation; ↑Cathepsins B,D, ↑M1 polarization, ↓M2 polarization; ↑Inflammation, fibrosis	Xu et al[272], Noureddin et al[277], Zhang et al[285], Dey et al[287]
Alcoholic liver disease	Acute ETOH administration: ↑Autophagy, ↑Mitophagy, ↑Lipophagy, ↑Proteophagy; Chronic ETOH administration: ↑ Autophagy (low dose), ↓Autophagy (high dose); Kupffer cells: ↓Autophagy, ↑Autophagy; HSCs: ↓Autophagy, ↑Autophagy	Protection, protection, protection, →Clearance of Mallory-Denk bodies; →Protection, →Mitochondrial damage, Cell death; Liver damage, protection; Reduced fibrosis, increased fibrosis	Chao et al[308], Komatsu et al[311], Yan et al[314], Harada et al[318]
HBV	↑Autophagy, ↓Lysosomal acidification, ↑Mitophagy	↑Virus replication, ↓HBV degradation	Li et al[356], Tang et al[357], Luo et al[372], Wang et al[383]
HCV	↑Autophagy, ↓Lipophagy, ↑Mitophagy; ↑CMA	↑Virus replication, steatosis, ↑Virus replication, ↓Apoptosis, persitent infection, ↑Virus replication	Ferraris et al[387], Paul et al[395], Jassey et al[404], Ren et al[406]
Fibrosis-Cirrhosis	Hepatocytes: ↓Autophagy, ↓Lipophagy; Kupffer cells: ↓Mitophagy, or, ↑↑Mitophagy; HSCs: ↓Mitophagy, ↓Lipophagy, or, ↑Lipophagy, ↑Mitophagy; LSECs: ↑↓Autophagy; Ductular reaction: ↑Autophagy	↑Fibrosis, ↑Lipotoxicity, ↓TGFb, ↓Fibrosis; ↑TGFb, ↑Fibrosis; Pro-inflammatory anti-fibrotic: →Pro-fibrotic, →Pro-fibrotic, ↑Fibrosis, ↑Fibrosis	Zhang et al[437], Singh et al[438], Li et al[448], Sun et al[463]
HCC, “Double edge sword”	Induction stage: ↑CMA, ↑Autophagy; Late stages: ↑Autophagy, or, ↓Autophagy, ↑Mitophagy, ↑Lipophagy	Anti-oncogenic: ↓YAP1, ↓proliferation, ↑Apoptosis→Anti-oncogenic, ↓Tumor suppressors; ↑Tumor progression, ↓↑Progression↑↓Progression	Wang et al[558], Zhao et al[559], Prieto-Domínguez et al[560]; Niture et al[544], Yang et al[547]; Lin et al[549], Chen et al[550], Chen et al[551]
Cholangiocarcinoma	↑Autophagy	↑Tumor progression	Marciniak et al[580], Teckman et al[581]
A1 antitrypsin deficiency	↓Autophagy		Yamamura et al[590], Pastore et al[592]
Fibrinogen storage disease	↓Autophagy		Hu et al[609]
Wilson’S disease	↓Autophagy		Oami et al[611]
Glycogen storage disease	↓Autophagy		Xing et al[613]
Sepsis	Kupffer cells: ↑Autophagy, ↑↑Autophagy, ↓Mitophagy	M2 polarization, ↓Inflammasome activation; Kupffer cell apoptosis→Cytokine storm, ↓Apoptosis of CD4+ve T cells	Ying et al[615], Neumann et al[616], Sun et al[628], Shan et al[629]
Acetaminophene liver damage	↓Autophagy, ↓Mitophagy, ↑Kupffer cell autophagy	↑APAP-Protein adducts	Sydor et al[618], Kim et al[643], Biel et al[644]
Acute liver failure	↑Autophagy, ↓Autophagy, ↓HSCs Mitophagy	HMGB1→HSCs activation (protective); ↑NO,ROS→↓HSCs→Devastation	Cheong et al[649], Sridhar et al[652]
Ischemia/reperfusion injury	↓Autophagy		Kwak et al[658], Huang et al[659]
Hepatic encephalopathy	↑Autophagy (NH4)	Protection	Woolbright et al[663], Manley et al[666]
Autoimmune hepatitis	↑Autophagy, ↓ Mitophagy	Defective maturation of dendritic cells	Sasaki et al[671], Sasaki et al[672], Young et al[673]
Biliary disease (experimental)	↓Autophagy	Possibly through increased bile acids	Sasaki et al[665], European Association for the Study of the Liver[675], Lindor et al[676], Panzitt et al[680]
Primary biliay cholangitis	Deregulated autophagy	Cholangiocyte senescence	Van de Graaf et al[669], Sasaki et al[665], Sasaki et al[674]

Note the double edge sword behaviour of autophagy, particularly evident in hepatocellular carcinoma. Autophagy refers to macroautophagy. HSCs: Hepatic stellate cells; LSECs: Liver sinusoidal endothelial cells; CMA: Chaperone mediated autophagy; ER: Enoplamic reticulum; ASH: Acute alcoholic hepatitis.