Thorntonantonsen7740

C-mannosylation is a unique type of glycosylation. A disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS4) is a multidomain extracellular metalloproteinase that contains several potential C-mannosylation sites. Although some ADAMTS family proteins have been reported to be C-mannosylated proteins, whether C-mannosylation affects the activation and protease activity of these proteins is unclear.

We established wild-type and mutant ADAMTS4-overexpressing HT1080 cell lines. Recombinant ADAMTS4 was purified from the conditioned medium of the wild-type ADAMTS4-overexpressing cells, and the C-mannosylation sites of ADAMTS4 were identified by LC-MS/MS. The processing, secretion, and intracellular localization of ADAMTS4 were examined by immunoblot and immunofluorescence analyses. ADAMTS4 enzymatic activity was evaluated by assessing the cleavage of recombinant aggrecan.

We identified that ADAMTS4 is C-mannosylated at Trp

in the metalloprotease domain and at Trp

, Trp

, and Trp

in the thrombospondin type 1 repeat (TSR). The replacement of Trp

with Phe affected ADAMTS4 processing, without affecting secretion and intracellular localization. In contrast, the substitution of Trp

, Trp

, and Trp

with Phe residues suppressed ADAMTS4 secretion, processing, intracellular trafficking, and enzymatic activity.

Our results demonstrated that the C-mannosylation of ADAMTS4 plays important roles in protein processing, intracellular trafficking, secretion, and enzymatic activity.

Because C-mannosylation appears to regulate many ADAMTS4 functions, C-mannosylation may also affect other members of the ADAMTS superfamily.

Because C-mannosylation appears to regulate many ADAMTS4 functions, C-mannosylation may also affect other members of the ADAMTS superfamily.

Mitochondria is a key organelle for energy production and cellular adaptive response to intracellular and extracellular stresses. Mitochondrial stress can be evoked by various stimuli such as metabolic stressors or pathogen infection, which may lead to expression of 'mitokines' such as growth differentiation factor 15 (GDF15).

This review summarizes the mechanism of GDF15 expression in response to organelle stress such as mitochondrial stress, and covers pathophysiological conditions or diseases that are associated with elevated GDF15 level. This review also illustrates the in vivo role of GDF15 expression in those stress conditions or diseases, and a potential of GDF15 as a therapeutic agent against metabolic disorders such as NASH.

Mitochondrial unfolded protein response (UPRmt) is a critical process to recover from mitochondrial stress. UPRmt can induce expression of secretory proteins that can exert systemic effects (mitokines) as well as mitochondrial chaperons. GDF15 can have either protective or detrimental systemic effects in response to mitochondrial stresses, suggesting its role as a mitokine. Mounting evidence shows that GDF15 is also induced by stresses of organelles other than mitochondria such as endoplasmic reticulum (ER). GDF15 level is increased in serum or tissue of mice and human subjects with metabolic diseases such as obesity or NASH. GDF15 can modulate metabolic features of those diseases.

GDF15 play a role as an integrated stress response (ISR) beyond mitochondrial stress response. GDF15 is involved in the pathogenesis of metabolic diseases such as NASH, and also could be a candidate for therapeutic agent against those diseases.

GDF15 play a role as an integrated stress response (ISR) beyond mitochondrial stress response. GDF15 is involved in the pathogenesis of metabolic diseases such as NASH, and also could be a candidate for therapeutic agent against those diseases.

In recent years, many reports have highlighted that metabolic surgery may ameliorate the cardiovascular risk in morbidly obese patients with or without type 2 diabetes (T2D). However, few studies have evaluated the long-term cardiovascular disease (CVD) risk after metabolic surgery in T2D patients with a low body mass index (BMI).

To use the Prediction for ASCVD Risk in China (China-PAR) equations and United Kingdom Prospective Diabetes Study (UKPDS) risk engine to assess the 10-year CVD risk in low-BMI T2D patients after metabolic surgery.

University hospital, China.

We retrospectively reviewed our prospectively collected data of T2D patients who underwent metabolic surgery at our hospital between 2010 and 2018. We included patients who met the criteria for calculating a 10-year cardiovascular risk score by the China-PAR equations and UKPDS risk engine. Demographic characteristics, anthropometric variables, and glycolipid metabolic parameters were assessed preoperatively and during a 4-year follow-upthe UKPDS risk engine.

The 10-year CVD risk in T2D patients with BMIs < 30 kg/m

and BMIs > 30 kg/m

were significantly reduced after metabolic surgery, although the rate of complete T2D remission T2Din patients with BMIs < 30 kg/m

was lower than that in patients with BMIs > 30 kg/m

. The China-PAR equation is a reliable and useful clinical tool for CVD risk evaluation in Chinese patients after metabolic surgery.

30 kg/m2. The China-PAR equation is a reliable and useful clinical tool for CVD risk evaluation in Chinese patients after metabolic surgery.Palmitic acid (PA)-induced hepatocyte apoptosis is critical for the progression of nonalcoholic fatty liver disease (NAFLD). Zn-C3 supplier Inositol 1,4,5-trisphosphate receptor type 1 (IP3R1) is an intracellular Ca2+-release channel and is involved in PA-induced hepatocyte apoptosis. While the expression of IP3R1 is elevated in patients with NAFLD and in hepatocytes treated with PA, it remains unclear how PA promotes the expression of IP3R1. In present study, our results showed that PA induced mitochondrial dysfunction and apoptosis, which is accompanied with the increase of the IP3R1 expression in hepatic cells. The inhibition of IP3R1 expression using siRNA ameliorated the PA-induced mitochondrial dysfunction. Furthermore, PA enhanced the stability of the IP3R1 protein instead of an increase in its mRNA levels. PA also promoted the phosphorylation of IP3R1 at the Tyr353 site and increased the phosphorylation of src in hepatic cells. Moreover, an inhibitor of src kinase (SU6656) significantly reduced the Tyr353 phosphorylation of IP3R1 and decreased its stability.