Abnormality of autophagic function and cathepsin expression in the liver from patients with non‐alcoholic fatty liver disease

Fukuo, Yuka; Yamashina, Shunhei; Sonoue, Hiroshi; Arakawa, Atsushi; Nakadera, Eisuke; Aoyama, Tomonori; Uchiyama, Akira; Kon, Kazuyoshi; Ikejima, Kenichi; Watanabe, Sumio

doi:10.1111/hepr.12282

Cited by 151 publications

(97 citation statements)

References 37 publications

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“…Several mechanisms may account for this decline in autophagy [112]: (1) increased degradation of autophagy-related gene-7 by an obesity-induced calcium-dependent protease calpain-2 [111]; (2) hyperactivation of the mammalian/mechanistic target of rapamycin signaling, a major autophagy inhibitory pathway, by increased amino acid flux into hepatocytes following overnutrition [113]; and (3) a defect in lysosomal acidification and reduction in cathepsin L that impairs substrate degradation in autolysosomes [114]. Cathepsin B, D, and L expression levels are significantly decreased in the liver of NAFLD patients [115]. Obesity-associated alterations in other signaling pathways may also regulate autophagy to influence NAFLD development and progression, particularly pathways involved in energy sensing of cells, such as AMPK and PI3K.…”

Section: Autophagy and Fatty Livermentioning

confidence: 99%

Molecular mechanisms of fatty liver in obesity

Xiang

Xie

2015

Front. Med.

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Nonalcoholic fatty liver disease (NAFLD) covers a spectrum of liver disorders ranging from simple steatosis to advanced pathologies, including nonalcoholic steatohepatitis and cirrhosis. NAFLD significantly contributes to morbidity and mortality in developed societies. Insulin resistance associated with central obesity is the major cause of hepatic steatosis, which is characterized by excessive accumulation of triglyceride-rich lipid droplets in the liver. Accumulating evidence supports that dysregulation of adipose lipolysis and liver de novo lipogenesis (DNL) plays a key role in driving hepatic steatosis. In this work, we reviewed the molecular mechanisms responsible for enhanced adipose lipolysis and increased hepatic DNL that lead to hepatic lipid accumulation in the context of obesity. Delineation of these mechanisms holds promise for developing novel avenues against NAFLD.

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Section: Autophagy and Fatty Livermentioning

confidence: 99%

Molecular mechanisms of fatty liver in obesity

Xiang

Xie

2015

Front. Med.

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“…Indeed, we have also reported that the number of autophagic vesicles in hepatocytes was increased in NAFLD patients 19) . Additionally, our collaborators have demonstrated that liver-specific autophagydeficient mice harbor adenomas linked to both the formation of p62-and Keap1-positive cellular aggregates and induction of Nrf2 targets (Figure-8).…”

Section: Autophagy Dysregulation In Pathogenesis Of Nashmentioning

confidence: 78%

Pathophysiology of Nonalcoholic Steatohepatitis

Watanabe

2017

Juntendo Medical Journal

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Nonalcoholic steatohepatitis (NASH), occurs frequently with diabetes mellitus and obesity, contributes to insulin resistance, can develop cirrhosis or even hepatocellular carcinoma (HCC). Although NASH has become more common, its underlying mechanism is still not clear and effective therapy has not been established.Currently, it has been recognized that the multiple parallel factors, including genetic differences, insulin resistance, lipotoxicity and dysbiosis act synergistically in genetically in pathogenesis of NASH. Impaired autophagy parallel to excess lipid supply might explain the progression of NASH to HCC. Liver-specific knockout mice of phosphatase and tensin homolog deleted on chromosome ten (PTEN) develops steatohepatitis followed by HCC, suggesting a potential role for this molecule in development and progression of NASH.

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“…However, some authors did not observe an atenuated fusion capacity. Instead, they report a decrease in clearance of autophagosomes due to a disturbed acidiication of lysosomal compartments [96,97] and/or downregulated cathepsin expression [71,96].…”

Section: Contextual Variability Of Autophagy In Lipid Metabolismmentioning

confidence: 99%

“…Nonetheless, a small post-mortem study demonstrated decreased LC3 and increased p6 staining in relation with the degree of steatosis, suggesting decreased autophagy in more severe steatosis [37]. Likewise, in proven N"FLD p6 accumulation, increased numbers of autophagic vesicles were demonstrated [71]. mRN" and protein analysis of liver biopsies were also indicative of an impaired autophagic lux in both N"FL and N"SH patients [7 ]. "…”

Section: Autophagy As a Lipolytic Mechanismmentioning

confidence: 99%

Autophagy in Non-Alcoholic Fatty Liver Disease (NAFLD)

Kwanten¹,

Martinet²,

Francque³

2016

Autophagy in Current Trends in Cellular Physiology and Pathology

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Abstract"utophagy is a mechanism involved in cellular homeostasis under basal and stressed conditions delivering cytoplasmic content to the lysosomes for degradation to macronutrients. The potential role of autophagy in disease is increasingly recognised and investigated. To date, a key role of autophagy in hepatic lipid metabolism is recognised and dysfunctional autophagy might be an underlying cause of non-alcoholic faty liver disease N"FLD . Nevertheless, the exact role of autophagy in lipid metabolism remains controversial, with both a lipolytic function of autophagy and lipogenic function reported. This chapter aims to review the current knowledge on autophagy in N"FLD, with a special focus on its role in hepatic lipid metabolism, hepatic glucose metabolism and insulin resistance, steatohepatitis, hepatocellular injury and hepatic ibrogenesis. Finally, interaction with another cellular homeostatic process, the unfolded protein response UPR , will be briely discussed.

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Abnormality of autophagic function and cathepsin expression in the liver from patients with non‐alcoholic fatty liver disease

Cited by 151 publications

References 37 publications

Molecular mechanisms of fatty liver in obesity

Molecular mechanisms of fatty liver in obesity

Pathophysiology of Nonalcoholic Steatohepatitis

Autophagy in Non-Alcoholic Fatty Liver Disease (NAFLD)

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