Cathepsin B overexpression induces degradation of perilipin 1 to cause lipid metabolism dysfunction in adipocytes

Abstract

Obesity, caused by the dysfunction of white adipose tissue (WAT), is reportedly accompanied by exacerbation of lipolysis. Perilipin 1 (PLIN1), which forms a coat around lipid droplets, interacts with several lipolysis proteins to regulate lipolysis. While it is known that perilipin family proteins are degraded in lysosomes, the underlying molecular mechanisms related to the downregulated expression of PLIN1 in obese WAT remain unknown. Recently, we found that lysosomal dysfunction originating from an abnormality of cathepsin B (CTSB), a lysosomal representative protease, occurs in obese WAT. Therefore, we investigated the effect of CTSB alterations on PLIN1 expression in obese WAT. PLIN1 protein disappeared and CTSB protein appeared in the cytoplasm of adipocytes in the early stage of obese WAT. Overexpression of CTSB reduced PLIN1 protein in 3T3L1 adipocytes, and treatment with a CTSB inhibitor significantly recovered this reduction. In addition, CTSB overexpression induced the dysfunction of lipolysis in 3T3L1 adipocytes. Therefore, we concluded that upregulation of CTSB induced the reduction of PLIN1 protein in obese WAT, resulting in lipolysis dysfunction. This suggests a novel pathology of lipid metabolism involving PLIN1 in adipocytes and that CTSB might be a therapeutic candidate molecule for obese WAT.

Insights Into Transcriptome Profiles Associated With Wooden Breast Myopathy in Broilers Slaughtered at the Age of 6 or 7 Weeks

“…The up-regulation of CTSB was previously associated with an enhanced activity of cathepsin B and L in WB breasts measured 12 h postmortem ( Hasegawa et al, 2020 ). In addition, Mizunoe et al (2020) recently reported that an overexpressed CTSB caused dysfunction of lipid metabolism in obese white adipose tissue potentially through a chronic state of low-grade inflammation, which was relevant to the condition of WB myopathy. Tubulins, dynamic polymers of microtubules, play important roles in various cellular functions through continual cytoskeletal reorganization in response to developmental and environmental cues ( Ambriz et al, 2018 ).…”

Cathepsin gene expression in abdominal subcutaneous adipose tissue of obese/overweight humans

“…The lysosomal proteases CTSB and CTSL1 are active as cysteine endo- and exopeptidase, which are abundantly expressed at the gene and protein level in human adipose tissue [ 8 , 18 ]. High expression of CTSB might contribute to increased basal lipolysis and a possible subsequent inflammatory response via reduce PLIN1 expression as shown in 3T3L-1 adipocytes [ 19 ]. Previously, observations in a relatively small study (n = 9) showed that CTSB gene expression is upregulated in SCAT of obese compared to lean 21–35 years-old men [ 20 ].…”

Wild-type GBA1 increases the α-synuclein tetramer–monomer ratio, reduces lipid-rich aggregates, and attenuates motor and cognitive deficits in mice

“…Two-way ANOVA revealed a significant interaction [ F (1,20) = 16; P < 0.001] and post hoc paired comparison showed that the excess NileR+ positive foci were decreased in the 3K-wtGBA1 versus 3K-vec mice ( P < 0.01) and became more similar to the (unchanged) NileR+ puncta detected in Ntg mice. Additionally, Plin2, a coat protein whose binding shields LDs from cytosolic degradation, if not being stripped off by lysosomal proteases ( 33 , 34 ), formed numerous immunoreactive foci in 3K-vec mouse brains. This suggests a decrease in lysosomal lipophagy in 3K brain, as we previously observed ( 22 ).…”

“…We next examined immunoreactivity for cathepsin B (CatB), an enzyme that undergoes maturation to its active form by autocleavage at low pH ( 39 ). Interestingly, mature CatB can strip off Plins from the LDs when localized to the lysosomal membrane ( 34 ). Of note, decreased CatB immunoreactivity and maturation have been described in induced pluripotent stem cells–derived neurons from GBA1-mutant PD patients ( 40 ).…”