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

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.

Trehalose protects against oxidative stress by regulating the Keap1-Nrf2 and autophagy pathways.

Dysfunction of autophagy, which regulates cellular homeostasis by degrading organelles and proteins, is associated with pathogenesis of various diseases such as cancer, neurodegeneration and metabolic disease. Trehalose, a naturally occurring nontoxic disaccharide found in plants, insects, microorganisms and invertebrates, but not in mammals, was reported to function as a mechanistic target of the rapamycin (mTOR)-independent inducer of autophagy. In addition, trehalose functions as an antioxidant though its underlying molecular mechanisms remain unclear. In this study, we showed that trehalose not only promoted autophagy, but also increased p62 protein expression, in an autophagy-independent manner. In addition, trehalose increased nuclear translocation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in a p62-dependent manner and enhance expression of its downstream antioxidant factors, heme oxygenase-1 (Ho-1) and nicotinamide adenine dinucleotide phosphate quinone dehydrogenase 1 (Nqo1). Moreover, treatment with trehalose significantly reduced amount of reactive oxygen species. Collectively, these results suggested that trehalose can function as a novel activator of the p62-Keap1/Nrf2 pathway, in addition to inducing autophagy. Therefore, trehalose may be useful to treat many chronic diseases involving oxidative stress and dysfunction of autophagy.