Emerging Roles of Impaired Autophagy in Fatty Liver Disease and Hepatocellular Carcinoma

Table 1

Impaired autophagic function in NAFLD, AFLD, and HCC.

Liver disease	Impaired autophagy function	Ref.
NAFLD	Hepatic steatosis in mice blocks autophagic proteolysis via impairment of autophagosomal acidification and cathepsin expression.	[54]
NAFLD	Animal fed with high-fat diet reduces autophagosome/lysosome fusion by 70% compared with animals fed with a normal diet.	[57]
NAFLD	In diabetic/ob/ob mice, HFD increased insulin resistance and hyperinsulinemia leading to impaired autophagic function caused by downregulation of autophagy regulatory gene expression.	[53]
NAFLD	Mice fed with HFD or patients with NAFLD show increased expression of Rubicon impairing the autophagic process in liver tissues.	[58]
NAFLD	Mice or hepatocytes treated with palmitic fatty acid show inhibition of ATP2A2/SERCA2, an ER-calcium pump, leading to increasing in cytosolic calcium levels and impaired autophagic flux due to interference calcium in the fusion of autophagosomes with lysosomes.	[59]
NAFLD	Hepatocytes treated with methionine and S-adenosylmethionine activated PP2A by methylation, leading to impaired autophagic catabolism and hence increased liver steatosis.	[61]
NAFLD	Genetic ablation of PLD1 in mice decreased the expression of Cpt1a, PPAR-α, Acat1, AcadV1, and increased impaired autophagic flux (p62 and LC3-II) and enhancing hepatic triglyceride accumulation in liver samples.	[62]
NAFLD	Mice fed with HFD containing saturated fatty acids, show increased SIRT3, inactivation of AMPK1, and activation of mTOR, leading to impaired autophagic function and increased lipotoxicity in the liver.	[63]
NAFLD/NASH	Hepatocytes exposed to saturated fatty acids showed increased activation of TBK1. TBK1 phosphorylated p62, inducing impaired autophagy leading to aggregation of ubiquitinated proteins and protein inclusions, increasing lipotoxicity in hepatocytes.	[64]
NAFLD	Mice fed with HFD or Huh7 hepatic cells treated with palmitic acid, showed increased expression of p62, LC3-II, and accumulation of autophagosomes, suggesting a defective autophagic flux.	[37]
NAFLD steatosis/NASH	ER stress enhanced IBTKα, LC3B, SEC16A, and SEC31A localization on ER and initiated phagophore formation, whereas, induction of IBTKα and inhibition of autophagic flux was associated with steatosis to NASH transition in NAFLD.	[65]
NAFLD	Increased autophagic vesicles and decreased cathepsin B, D, and L protease activities were detected in human NAFLD patients suggesting that hepatic steatosis induced impaired autophagy in the liver and reduced autophagic proteolysis.	[55]
AFLD	Chronic ethanol exposure activated mTORC1, downregulated TFEB-mediated lysosomal gene expression, and lysosomal biogenesis leading to defective autophagy in mice liver.	[74]
AFLD	Hepatic cells or mice chronically exposed to ethanol, show inhibition of AMPK, activation of ACC activity, and increased malonyl CoA content in liver tissues due to the suppression of autophagy.	[87]
AFLD	Rats fed with chronic ethanol downregulates Beclin-1 and ATG5 expression and upregulated p62 in liver tissues, indicating impaired autophagic function.	[88]
AFLD	Chronic ethanol exposure in rats inactivated Rab 7 and dynamin 2 activities resulting in impaired lipophagy.	[89, 90]
AFLD	Chronic ethanol exposure in rats decreased activities of lysosomal acid phosphatase, beta-galactosidase, and intralysosomal hydrolase activity in rat hepatocytes.	[91]
HCC	HCC tumors or HCC cells show higher expression of p62 and glypican-3 indicating defective autophagy liver cancer.	[99]
HCC	Impairing autophagy by ATG5 knockdown in hepatocytes increased oxidative stress and DNA damage leading to initiation of hepatocarcinogenesis.	[100]
HCC	Human antigen R increased ATG5, ATG12, and ATG16 transcripts leading to defective autophagy in HCC cells.	[103]
HCC	Deficiency of ATG5 and ATG7 genes induced impaired autophagy and increased development of benign liver adenomas in mice.	[104]
HCC	The deletion of the Beclin 1 gene in mice impaired the autophagic process increasing the incidence of spontaneous tumors.	[105]
HCC	Treatment of sorafenib induced autophagy, whereas the deletion of ATG7 impaired autophagic function leading to increased sensitivity of HCC cells towards antiliver cancer drugs.	[109]