“膏-浊-热毒”病机演变是高脂血症性急性胰腺炎（HTG-AP）重症化核心机制：AP发生前，脂质代谢紊乱，脂肪储存蛋白（FIT2）和脂解酶（HSL）异常，游离脂肪酸（FFA）基线水平升高，出现“膏化浊邪”的代谢性炎症；AP发生时，胰脂肪酶和组蛋白引起胰腺脂肪脂解，大量FFA释放，“浊聚化热变毒”引起细胞坏死和炎症级联反应。我们发现，临床验方柴芩承气汤（CQCQD）抑制胰脂肪酶和组蛋白减少脂解和FFA释放；HTG小鼠胰腺脂肪FIT2表达增高，伴内质网应激（ERS），诱导AP后胰腺脂肪FIT2表达显著下降、ERS增强。结合抑制HSL、减少脂解改善代谢性炎症的报道，本项目拟首次从脂肪细胞代谢环节FIT2/HSL-FFA即“膏浊互化、浊邪变毒”的角度，探索HTG-AP重症化机制，验证CQCQD抑制脂解减少“热毒”FFA释放的保护作用，阐释“膏-浊-热毒”病机演变和CQCQD“涤浊伐毒”的疗效机制。

We postulate that “fat-turbidity-toxic heat” pathogenesis is the core mechanism for hypertriglyceridemia acute pancreatitis (HTG-AP). There are two lines of evidence to support this hypothesis: Lipid disorder is a condition associated with excess release of free fatty acids (FFAs) caused by dysfunction of key lipid metabolism proteins namely fat storage-inducing transmembrane protein 2 (FIT2) and hormone-sensitive lipase (HSL). It has been shown that chronic elevation of baseline FFA will lead to metabolically triggered inflammation (meta-inflammation). The comorbid meta-inflammation will acerbate severity of HTG-AP when it occurs; During AP, the influx of large amount of FFAs from pancreatic adipose tissue lipolysis caused by pancreatic lipase and extracellular histones, has been demonstrated to cause cellular necrosis and inflammatory cascade. Our recent work has revealed that chaiqin chengqi decoction (CQCQD) suppressed pancreatic lipase/histone-medicated lipolysis and FFA release from adipose cell line 3T3-L1. Further, increased FIT2 mRNA expression and endoplasmic reticulum stress (ERS) were observed in pancreatic adipose tissue obtained from high fat-fed mice compared with those without high fat. Whereas, the FIT2 mRNA expression was dramatically reduced to a level that was significantly lower than normal controls shortly after induction of AP. This loss of FIT2 mRNA expression was accompanied by more intensified ERS compared with caerulein or high fat administration alone. In the light of our new results and the fact that HSL partial inhibition can reduce lipolysis and resultant meta-inflammation, in this program, we seek to: (1) investigate the role of adipocytic FIT2/HSL-FFA-medicated lipid metabolism pathways in HTG-AP; (2) verify protective effects of CQCQD on HTG-AP via inhibition of lipolysis and release of FFAs. Our hypothesis and results from this work will provide a better understanding of pathogenesis for HTG-AP and the therapeutic targets of CQCQD.