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Review
. 2019 Jul 27;20(15):3688.
doi: 10.3390/ijms20153688.

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

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Free PMC article
Review

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

Yuhei Mizunoe et al. Int J Mol Sci. .
Free PMC article

Abstract

Obesity causes various health problems, such as type 2 diabetes, non-alcoholic fatty liver disease, and cardio- and cerebrovascular diseases. Metabolic organs, particularly white adipose tissue (WAT) and liver, are deeply involved in obesity. WAT contains many adipocytes with energy storage capacity and secretes adipokines depending on the obesity state, while liver plays pivotal roles in glucose and lipid metabolism. This review outlines and underscores the relationship between obesity and lysosomal functions, including lysosome biogenesis, maturation and activity of lysosomal proteases in WAT and liver. It has been revealed that obesity-induced abnormalities of lysosomal proteases contribute to inflammation and cellular senescence in adipocytes. Previous reports have demonstrated obesity-induced ectopic lipid accumulation in liver is associated with abnormality of lysosomal proteases as well as other lysosomal enzymes. These studies demonstrate that lysosomal dysfunction in WAT and liver underlies part of the obesity-related pathology, raising the possibility that strategies to modulate lysosomal function may be effective in preventing or treating the metabolic syndrome.

Keywords: adipose tissue; cathepsin; liver; lysosomal dysfunction; lysosome.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Lysosomal dysfunction in obese adipose tissue. In obese adipose tissue, various stresses such as oxidative stress and lysosomal pH abnormality attenuate the maturation of cathepsin L (CTSL) protein, leading to complementary activation of CTSB. Downregulation of CTSL protein causes the accumulation of autophagosomes, resulting in suppression of autophagic clearance. Upregulation of CTSB protein enhances inflammation by activating the inflammasome complex. These lysosomal alterations consequently affect the function of white adipose tissue (WAT).
Figure 2
Figure 2
Lysosomal dysfunction in obese liver. In obese liver, various stresses such as lipotoxicity and endoplasmic reticulum (ER) stress alkalinizes the lysosomal pH, resulting in downregulated activity of cathepsin L (CTSL), CTSB and CTSD. Downregulation of cathepsins induce autophagosome accumulation due to impaired lysosomal clearance. Hepatic lysosomal lipase (LAL) is associated with the progression of non-alcoholic fatty liver disease (NAFLD). These lysosomal abnormalities contribute to the onset of NAFLD.

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References

    1. Van Gaal L.F., Mertens I.L., de Block C.E. Mechanisms linking obesity with cardiovascular disease. Nature. 2006;444:875–880. doi: 10.1038/nature05487. - DOI - PubMed
    1. Schwartz M.W., Seeley R.J., Zeltser L.M., Drewnowski A., Ravussin E., Redman L.M., Leibel R.L. Obesity Pathogenesis: An Endocrine Society Scientific Statement. Endocr. Rev. 2017;38:267–296. doi: 10.1210/er.2017-00111. - DOI - PMC - PubMed
    1. Rutkowski J.M., Stern J.H., Scherer P.E. The cell biology of fat expansion. J. Cell Biol. 2015;208:501–512. doi: 10.1083/jcb.201409063. - DOI - PMC - PubMed
    1. Heymsfield S.B., Wadden T.A. Mechanisms, Pathophysiology, and Management of Obesity. N. Engl. J. Med. 2017;376:254–266. doi: 10.1056/NEJMra1514009. - DOI - PubMed
    1. Ouchi N., Parker J.L., Lugus J.J., Walsh K. Adipokines in inflammation and metabolic disease. Nat. Rev. Immunol. 2011;11:85–97. doi: 10.1038/nri2921. - DOI - PMC - PubMed

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