High-fat and high-cholesterol diet decreases phosphorylated inositol-requiring kinase-1 and inhibits autophagy process in rat liver

Naito, Hisao; Yoshikawa-Bando, Yuki; Yuan, Yuan; Hashimoto, Sayuki; Kitamori, Kazuya; Yatsuya, Hiroshi; Nakajima, Tamie

doi:10.1038/s41598-019-48973-w

Cited by 13 publications

(9 citation statements)

References 53 publications

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“…These results are consistent with the study of Stoeck et al [30], showing that HCV replication promotes cholesterol homeostasis. The accumulation of longer fatty acids and cholesterol in the infected cells could inhibit the ubiquitin-dependent protein degradation pathway; therefore, increases ER stress [31]. These results are in agreement with another study showing that HCV-induced cholesterol biosynthesis increases ER stress, steatohepatitis, and increases incidence HCC in HCV core transgenic mice [32].…”

Section: Hepatocytes Experience Multifaceted Stress Responses Durisupporting

confidence: 84%

Chaperone-Mediated Autophagy in the Liver: Good or Bad?

Dash

Aydın

Moroz

2019

Cells

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Hepatitis C virus (HCV) infection triggers autophagy processes, which help clear out the dysfunctional viral and cellular components that would otherwise inhibit the virus replication. Increased cellular autophagy may kill the infected cell and terminate the infection without proper regulation. The mechanism of autophagy regulation during liver disease progression in HCV infection is unclear. The autophagy research has gained a lot of attention recently since autophagy impairment is associated with the development of hepatocellular carcinoma (HCC). Macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA) are three autophagy processes involved in the lysosomal degradation and extracellular release of cytosolic cargoes under excessive stress. Autophagy processes compensate for each other during extreme endoplasmic reticulum (ER) stress to promote host and microbe survival as well as HCC development in the highly stressed microenvironment of the cirrhotic liver. This review describes the molecular details of how excessive cellular stress generated during HCV infection activates CMA to improve cell survival. The pathological implications of stress-related CMA activation resulting in the loss of hepatic innate immunity and tumor suppressors, which are most often observed among cirrhotic patients with HCC, are discussed. The oncogenic cell programming through autophagy regulation initiated by a cytoplasmic virus may facilitate our understanding of HCC mechanisms related to non-viral etiologies and metabolic conditions such as uncontrolled type II diabetes. We propose that a better understanding of how excessive cellular stress leads to cancer through autophagy modulation may allow therapeutic development and early detection of HCC.

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Section: Hepatocytes Experience Multifaceted Stress Responses Durisupporting

confidence: 84%

Chaperone-Mediated Autophagy in the Liver: Good or Bad?

Dash

Aydın

Moroz

2019

Cells

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“…It is noteworthy that freeze fracture electron microscopy analysis revealed early autophagosomal structures to be cholesterol poor 9 , suggesting that cholesterol poor membranes are the principal source of membranes during autophagosome biogenesis. In agreement with this, cholesterol depletion with methyl-β cyclodextrin (MBCD) and statins have been reported to promote LC3 lipidation and its turnover 10–15 . A few studies have however found that high cholesterol levels promote autophagy 16, 17 .…”

Section: Introductionmentioning

confidence: 56%

GRAMD1C regulates autophagy initiation and mitochondrial bioenergetics through ER-mitochondria cholesterol transport

Charsou

Lapao

et al. 2021

Preprint

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During autophagy, cytosolic cargo is sequestered into double-membrane vesicles called autophagosomes. The origin and identity of the membranes that from the autophagosome remain to be fully characterized. Here, we investigated the role of cholesterol in starvation-induced autophagy and identify a role for the ER-localized cholesterol transport protein GRAMD1C in the regulation of autophagy and mitochondrial function. We demonstrate first that cholesterol depletion leads to a rapid induction of autophagy, possibly caused by an increased abundance of curved autophagy membranes. We further show that GRAMD1C is a negative regulator of starvation-induced autophagy. Similar to its yeast orthologue, GRAMD1C is recruited to mitochondria through its GRAM domain. Additionally, we find that GRAMD1C is involved in mitochondrial cholesterol transfer and the regulation of mitochondrial bioenergetics. Finally, we demonstrate that the GRAM family are genes involved in clear cell renal carcinoma survival, highlighting the pathophysiological relevance of cholesterol transport proteins.

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“…Numerous studies have proved that CHO take an essential role in autophagy [ 22 , 23 ]. Meanwhile, autophagy plays a remarkable role in NAFLD progression [ 24 ].…”

Section: Resultsmentioning

confidence: 99%

“…This study was the first to obtain insights into the relationship between LAP3 and NASH induced by HFD. Meanwhile, NAFLD is characterized by excessive hepatic lipid accumulation with significant elevation of TC, TG, LDL, LDL/HDL, TG/HDL, TC/HDL, and lower HDL, accompanied by obesity, type 2 diabetes, compared to subjects without NAFLD [ 23 , 26 , 28 ]. Consistently, we firstly found that LAP3 expression was positively correlated with GGT, fasting blood glucose, while negatively correlated with HDL levels.…”

Section: Discussionmentioning

confidence: 99%

Cholesterol-induced leucine aminopeptidase 3 (LAP3) upregulation inhibits cell autophagy in pathogenesis of NAFLD

Feng

Chen

et al. 2022

Aging

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Objectives: Leucine aminopeptidase 3 (LAP3), an M1 member of leucine aminopeptidase, was reported to be significantly upregulated in serum of nonalcoholic fatty liver disease (NAFLD) patients. However, the underlying mechanisms of LAP3 in NAFLD pathogenesis are still unknown. We aim to investigate the role of LAP3 in NAFLD pathogenesis and explore whether LAP3 has the potential to be a candidate biomarker in serum for NAFLD diagnosis. Methods: Liver tissues and serum from NASH rats, serum from patients with NAFLD were obtained to evaluate the LAP3 expression. Detection of GSSG/GSH, intracellular reactive oxygen species (ROS), and LC3 expression by elevation/ reduction of LAP3 expression to determine the role of LAP3 in NAFLD pathogenesis. Finally, the correlation analysis was conducted to evaluate the association between LAP3 expression and clinical indexes of NAFLD. Results: LAP3 expression was upregulated in hepatocytes and serum in E3 rats with NASH after 6-month HFD feeding. Cholesterol (CHO) dramatically upregulated LAP3 in LO2 cells, and then lead to negative regulation of autophagy. Moreover, LAP3 levels were also significantly increased in NAFLD patients compared to healthy controls. Correlation analysis revealed that serum LAP3 levels were positively correlated with TG, γ-glutamyltranspeptidase (GGT), and fasting blood glucose levels, while there was a negative correlation with HDL levels. Conclusions: The cholesterol-dependent upregulation of LAP3 in hepatocytes plays a critical role in the pathogenesis of NAFLD via inhibiting autophagy. Moreover, LAP3 could serve as a potential novel candidate biomarker for the diagnosis of NAFLD.

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High-fat and high-cholesterol diet decreases phosphorylated inositol-requiring kinase-1 and inhibits autophagy process in rat liver

Cited by 13 publications

References 53 publications

Chaperone-Mediated Autophagy in the Liver: Good or Bad?

Chaperone-Mediated Autophagy in the Liver: Good or Bad?

GRAMD1C regulates autophagy initiation and mitochondrial bioenergetics through ER-mitochondria cholesterol transport

Cholesterol-induced leucine aminopeptidase 3 (LAP3) upregulation inhibits cell autophagy in pathogenesis of NAFLD

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