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

Niture, Suryakant K.; Lin, Meixia; Ríos-Colón, Leslimar; Qi, Qi; Moore, John T.; Kumar, Deepak

doi:10.1155/2021/6675762

Cited by 25 publications

(38 citation statements)

References 163 publications

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“… 19 Chronic exposure to viral and non-viral agents induces an integrated stress response which changes the cellular plasticity and cell fate. 10 , 54 At present many oncogenic processes have been implicated in HCC development including loss of tumor suppressors, angiogenesis, the immunosuppressive microenvironment in cirrhotic liver, inflammation, epigenetics modifications, and cancer stem cells. In addition, emerging new evidence indicates that angiogenesis and immunosuppressive microenvironment are frequently involved in HCC development.…”

Section: Discussionmentioning

confidence: 99%

“… 8 Furthermore, impairment of autophagy leads to hepatocellular carcinoma (HCC) development in several animal models and this effect has been demonstrated in cirrhotic livers with HCC. 9 , 10 Liver-specific deletion of autophagy genes (ATG5 or ATG7) caused a spectrum of hepatic diseases including steatosis, inflammation, fibrosis, hepatomegaly, and HCC. 11 , 12 Moreover, impaired autophagy promotes tumorigenesis in Beclin1 or LkB1 gene knockout mice livers.…”

Section: Introductionmentioning

confidence: 99%

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Impaired Autophagy Response in Hepatocellular Carcinomas Enriches Glypican-3 in Exosomes, Not in the Microvesicles

Köksal¹,

Thevenot²,

Aydın³

et al. 2022

JHC

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Background and Aim HCC development in liver cirrhosis is associated with impaired autophagy leading to increased production of extracellular vesicles (EVs) including exosomes and microvesicles. The goal of the study is to determine which of these particles is primarily involved in releasing of HCC-specific biomarker glypican-3 (GPC3) when autophagy is impaired. Methods Streptavidin-coated magnetic beads were coupled with either biotinylated CD63 or Annexin A1 antibodies. Coupled beads were incubated with EVs isolated from either HCC culture or serum. EVs captured by immuno-magnetic beads were then stained with FITC or PE fluorescent-conjugated antibodies targeting exosomes (CD81), and microvesicles (ARF6). The percentage of GPC3 enrichment in the microvesicles and exosomes was quantified by flow cytometry. The impact of autophagy modulation on GPC3 enrichment in exosomes and microvesicles was assessed by treating cells with Torin 1 and Bafilomycin A1. For clinical validation, GPC3 content was quantified in microvesicles, and exosomes were isolated from the serum of patients with a recent HCC diagnosis. Results The immune-magnetic bead assay distinguishes membrane-derived microvesicles from endosome-derived exosomes. The GPC3 expression was only seen in the CD63 beads group but not in the Annexin A1 beads group, confirming that in HCC, GPC3 is preferentially released through exosomes. Furthermore, we found that autophagy induction by Torin1 decreased GPC3-positive exosome secretion and decreased microvesicle release. Conversely, autophagy inhibition by Bafilomycin A1 increased the secretion of GPC3-positive exosomes. Serum analysis showed CD81+ve EVs were detected in exosomes and ARF6+ve vesicles were detected in microvesicles, suggesting that immunoaffinity assay is specific. The exosomal GPC3 enrichment was confirmed in isolated EVs from the serum of patients with HCC. The frequency of GPC3-positive exosomes was higher in patients with HCC (12.4%) compared to exosomes isolated from non-cirrhotic and healthy controls (3.7% and 1.3% respectively, p<0.001). Conclusion Our results show that GPC3 is enriched in the endolysosomal compartment and released in exosome fractions when autophagy is impaired.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Impaired Autophagy Response in Hepatocellular Carcinomas Enriches Glypican-3 in Exosomes, Not in the Microvesicles

Köksal¹,

Thevenot²,

Aydın³

et al. 2022

JHC

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“…However, large or chronic lipid exposure tends to deregulate the autophagy process [13,[16][17][18]. Accumulating evidence suggests that impaired autophagy prevents the clearance of LDs, damaged mitochondria, and toxic protein aggregates, which can be produced during the progression of various liver diseases, thus contributing to the development of steatosis, steatohepatitis, fibrosis, and cancer [19,20]. This supports the possibility that autophagy may be one of the key targets for the prevention and treatment of hepatic steatosis in NAFLD [21].…”

Section: Introductionmentioning

confidence: 86%

Posidonia oceanica (L.) Delile Extract Reduces Lipid Accumulation through Autophagy Activation in HepG2 Cells

2021

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Posidonia oceanica (L.) Delile is a marine plant traditionally used as an herbal medicine for various health disorders. P. oceanica leaf extract (POE) has been shown to be a phytocomplex with cell-safe bioactivities, including the ability to trigger autophagy. Autophagy is a key pathway to counteract non-alcoholic fatty liver disease (NAFLD) by controlling the breakdown of lipid droplets in the liver. The aim of this study was to explore the ability of POE to trigger autophagy and reduce lipid accumulation in human hepatoma (HepG2) cells and then verify the possible link between the effect of POE on lipid reduction and autophagy activation. Expression levels of autophagy markers were monitored by the Western blot technique in POE-treated HepG2 cells, whereas the extent of lipid accumulation in HepG2 cells was assessed by Oil red O staining. Chloroquine (CQ), an autophagy inhibitor, was used to study the relationship between POE-induced autophagy and intracellular lipid accumulation. POE was found to stimulate an autophagy flux over time in HepG2 cells by lowering the phosphorylation state of ribosomal protein S6, increasing Beclin-1 and LC3-II levels, and decreasing p62 levels. By blocking autophagy with CQ, the effect of POE on intracellular lipid accumulation was clearly reversed, suggesting that the POE phytocomplex may reduce lipid accumulation in HepG2 cells by activating the autophagic process. This work indicates that P. oceanica may be considered as a promising molecule supplier to discover new natural approaches for the management of NAFLD.

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“…Activating autophagy via increased AMPK phosphorylation, decreased mTOR, and increased LC3B expression [ 108 ]. Autophagy can prevent NAFLD and AFLD progression through enhanced lipid catabolism and decreased hepatic steatosis [ 109 ]. Our study observed the expression of p62 that actually appears to play a negative regulatory role in autophagy, and p62 accumulation is observed in the liver of ob/ob mice, and its aggregation is correlated with serum ALT activity and inflammatory activity by the NAFLD score [ 110 ].…”

Section: Discussionmentioning

confidence: 99%

The Ameliorative Effects of Saikosaponin in Thioacetamide-Induced Liver Injury and Non-Alcoholic Fatty Liver Disease in Mice

Chang

Lin

et al. 2021

IJMS

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Liver disorders are a major health concern. Saikosaponin-d (SSd) is an effective active ingredient extracted from Bupleurum falcatum, a traditional Chinese medicinal plant, with anti-inflammatory and antioxidant properties. However, its hepatoprotective properties and underlying mechanisms are unknown. We investigated the effects and underlying mechanisms of SSd treatment for thioacetamide (TAA)-induced liver injury and high-fat-diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) in male C57BL/6 mice. The SSd group showed significantly higher food intake, body weight, and hepatic antioxidative enzymes (catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD)) and lower hepatic cyclooxygenase-2 (COX-2), serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and fibroblast growth factor-21 (FGF21) compared with controls, as well as reduced expression of inflammation-related genes (nuclear factor kappa B (NF-κB) and inducible nitric oxide synthase (iNOS)) messenger RNA (mRNA). In NAFLD mice, SSd reduced serum ALT, AST, triglycerides, fatty acid–binding protein 4 (FABP4) and sterol regulatory element–binding protein 1 (SREBP1) mRNA, and endoplasmic reticulum (ER)-stress-related proteins (phosphorylated eukaryotic initiation factor 2α subunit (p-eIF2α), activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP). SSd has a hepatoprotective effect in liver injury by suppressing inflammatory responses and acting as an antioxidant.

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

Cited by 25 publications

References 163 publications

Impaired Autophagy Response in Hepatocellular Carcinomas Enriches Glypican-3 in Exosomes, Not in the Microvesicles

Impaired Autophagy Response in Hepatocellular Carcinomas Enriches Glypican-3 in Exosomes, Not in the Microvesicles

Posidonia oceanica (L.) Delile Extract Reduces Lipid Accumulation through Autophagy Activation in HepG2 Cells

The Ameliorative Effects of Saikosaponin in Thioacetamide-Induced Liver Injury and Non-Alcoholic Fatty Liver Disease in Mice

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