Association between Lysosomal Dysfunction and Obesity-Related Pathology: A Key Knowledge to Prevent Metabolic Syndrome

Mizunoe, Yuhei; Kobayashi, Masaki; Tagawa, Ryoma; Nakagawa, Yoshimi; Shimano, Hitoshi; Higami, Yoshikazu

doi:10.3390/ijms20153688

Cited by 31 publications

(22 citation statements)

References 117 publications

(133 reference statements)

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“…Lipoprotein accumulation and metabolism are important contributors to various diseases including cardiovascular diseases and obesity -associated disorders such as non-alcoholic steatohepatitis (NASH). Extracellular cathepsins are found to be involved in transport, efflux, and processing of lipoprotein molecules or their receptors (reviewed in [ 159 ]). For instance, extracellular cathepsins F, K, and S are known to degrade cholesterol acceptors on the cell surface, thereby reducing cholesterol efflux and initiating foam cell formation, a key feature of atherosclerosis [ 24 ].…”

Section: Cathepsins In the Extracellular Spacementioning

confidence: 99%

The Ins and Outs of Cathepsins: Physiological Function and Role in Disease Management

Yadati

Houben

Bitorina

et al. 2020

Cells

217

143

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Cathepsins are the most abundant lysosomal proteases that are mainly found in acidic endo/lysosomal compartments where they play a vital role in intracellular protein degradation, energy metabolism, and immune responses among a host of other functions. The discovery that cathepsins are secreted and remain functionally active outside of the lysosome has caused a paradigm shift. Contemporary research has unraveled many versatile functions of cathepsins in extralysosomal locations including cytosol and extracellular space. Nevertheless, extracellular cathepsins are majorly upregulated in pathological states and are implicated in a wide range of diseases including cancer and cardiovascular diseases. Taking advantage of the differential expression of the cathepsins during pathological conditions, much research is focused on using cathepsins as diagnostic markers and therapeutic targets. A tailored therapeutic approach using selective cathepsin inhibitors is constantly emerging to be safe and efficient. Moreover, recent development of proteomic-based approaches for the identification of novel physiological substrates offers a major opportunity to understand the mechanism of cathepsin action. In this review, we summarize the available evidence regarding the role of cathepsins in health and disease, discuss their potential as biomarkers of disease progression, and shed light on the potential of extracellular cathepsin inhibitors as safe therapeutic tools.

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Section: Cathepsins In the Extracellular Spacementioning

confidence: 99%

The Ins and Outs of Cathepsins: Physiological Function and Role in Disease Management

Yadati

Houben

Bitorina

et al. 2020

Cells

217

143

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“…The inhibition of CTSs has been widely explored over the last decades in the field of chronic inflammatory diseases [27,37,204,205], cardiovascular diseases [10,19,181], osteoporosis [70][71][72][73], arthritis [28,206], kidney diseases [30][31][32]84], pancreatitis [207], obesity [208][209][210], cancer [25,34,48,74,82,211], neurodegenerative diseases [39,41,184,185,212,213], and many other pathological states. Multiple inhibitors are currently available, ranging from reversible covalent inhibitors to irreversible inhibitors [214][215][216][217][218] (Table 4).…”

Section: Cathepsin Inhibitors and Their Therapeutic Applicationsmentioning

confidence: 99%

Cathepsins in the Pathophysiology of Mucopolysaccharidoses: New Perspectives for Therapy

Pasquale

Moles

Pavone

2020

Cells

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Cathepsins (CTSs) are ubiquitously expressed proteases normally found in the endolysosomal compartment where they mediate protein degradation and turnover. However, CTSs are also found in the cytoplasm, nucleus, and extracellular matrix where they actively participate in cell signaling, protein processing, and trafficking through the plasma and nuclear membranes and between intracellular organelles. Dysregulation in CTS expression and/or activity disrupts cellular homeostasis, thus contributing to many human diseases, including inflammatory and cardiovascular diseases, neurodegenerative disorders, diabetes, obesity, cancer, kidney dysfunction, and others. This review aimed to highlight the involvement of CTSs in inherited lysosomal storage disorders, with a primary focus to the emerging evidence on the role of CTSs in the pathophysiology of Mucopolysaccharidoses (MPSs). These latter diseases are characterized by severe neurological, skeletal and cardiovascular phenotypes, and no effective cure exists to date. The advance in the knowledge of the molecular mechanisms underlying the activity of CTSs in MPSs may open a new challenge for the development of novel therapeutic approaches for the cure of such intractable diseases.

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“…An extensive review of lysosomal enzyme abnormalities in both adipose and liver tissue was recently published[ 214 ]. A recent report suggests an additional mechanism contributing to obesity-associated abnormalities.…”

Section: Obesity Steatosis and Nafldmentioning

confidence: 99%

Autophagy in liver diseases

Kouroumalis

Voumvouraki

Augoustaki

et al. 2021

WJH

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Autophagy is the liver cell energy recycling system regulating a variety of homeostatic mechanisms. Damaged organelles, lipids and proteins are degraded in the lysosomes and their elements are re-used by the cell. Investigations on autophagy have led to the award of two Nobel Prizes and a health of important reports. In this review we describe the fundamental functions of autophagy in the liver including new data on the regulation of autophagy. Moreover we emphasize the fact that autophagy acts like a two edge sword in many occasions with the most prominent paradigm being its involvement in the initiation and progress of hepatocellular carcinoma. We also focused to the implication of autophagy and its specialized forms of lipophagy and mitophagy in the pathogenesis of various liver diseases. We analyzed autophagy not only in well studied diseases, like alcoholic and nonalcoholic fatty liver and liver fibrosis but also in viral hepatitis, biliary diseases, autoimmune hepatitis and rare diseases including inherited metabolic diseases and also acetaminophene hepatotoxicity. We also stressed the different consequences that activation or impairment of autophagy may have in hepatocytes as opposed to Kupffer cells, sinusoidal endothelial cells or hepatic stellate cells. Finally, we analyzed the limited clinical data compared to the extensive experimental evidence and the possible future therapeutic interventions based on autophagy manipulation.

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Association between Lysosomal Dysfunction and Obesity-Related Pathology: A Key Knowledge to Prevent Metabolic Syndrome

Cited by 31 publications

References 117 publications

The Ins and Outs of Cathepsins: Physiological Function and Role in Disease Management

The Ins and Outs of Cathepsins: Physiological Function and Role in Disease Management

Cathepsins in the Pathophysiology of Mucopolysaccharidoses: New Perspectives for Therapy

Autophagy in liver diseases

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