ATP5O Hypo-crotonylation Caused by HDAC2 Hyper-Phosphorylation Is a Primary Detrimental Factor for Downregulated Phospholipid Metabolism under Chronic Stress.

Objective. Chronic stress (CS)-induced abnormal metabolism and other subsequent aspects of abnormality are threatening human health. Little is known regarding whether and how protein post-translational-modifications (PTMs) correlate with abnormal metabolism under CS. The aim of this study was to address this issue and also identify novel key protein PTM. Methods. First, we screened which pan-PTM had significant change between control and CS female mice and whether clinical CS females had similar pan-PTM change. Second, we performed quantitative PTM-omics and metabolomics to verify the correlation between abnormal protein PTMs and atypical metabolism. Third, we performed quantitative phospho-omics to identify the key PTM-regulating enzyme and investigate the interaction between PTM protein and PTM-regulating enzyme. Fourth, we attempted to rectify the abnormal metabolism by correcting the activity of the PTM-regulating enzyme. Finally, we examined whether the selected key protein was also correlated with stress scores and atypical metabolism in clinical women. Results. We initially found that multiple tissues of CS female mice have downregulated pan-crotonylation, and verified that the plasma of clinical CS females also had downregulated pan-crotonylation. Then we determined that ATP5O-K51 crotonylation decreased the most and also caused gross ATP5O decrement, whereas the plasma of CS mice had downregulated phospholipids. Next, downregulating ATP5O crotonylation partially recapitulated the downregulated phospholipid metabolism in CS mice. Next, we verified that HDAC2-S424 phosphorylation determined its decrotonylation activity on ATP5O-K51. Furthermore, correcting HDAC2 hyper-phosphorylation recovered the gross ATP5O level and partially rescued the downregulated phospholipid metabolism in CS mice. Finally, the ATP5O level was also significantly lower and correlated with high stress scores and downregulated phospholipid metabolism in clinical female plasma. Conclusion. This study discovered a novel PTM mechanism involving two distinct types of PTM in CS and provided a novel reference for the clinical precautions and treatments of CS.

Circulating ghrelin in patients with gastric or colorectal cancer.

The purpose of this study was to investigate the pathophysiologic change of ghrelin in gastric and colorectal cancer patients, especially in those with cachexia. Fifty-eight gastric cancer patients, 20 colorectal cancer patients, and 24 healthy control individuals were included in this study. Thirty-one patients were defined as cachectic, based on the percentage of weight loss versus the previous normal weight. The remaining 47 patients were defined as noncachectic. Peripheral hormones, including ghrelin, insulin, leptin, growth hormone, glucagon, and cortisol, and body composition parameters were measured. Plasma ghrelin levels did not increase significantly in cachectic gastric (p = 0.352) or colorectal (p = 0.871) cancer patients as compared with controls and were not correlated with nutrition status and other hormones. The location of gastric cancer (proximal vs. distal) had no influence on ghrelin levels (p = 0.966). These findings suggest that gastric and colorectal cancers may have their special effects on the production of ghrelin. Gastric or colorectal cancer cachexia may be partly due to the lack of increase in ghrelin, which makes exogenous ghrelin therapy feasible in this setting.