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Increase in plasma Niemann-Pick disease type C2 protein is associated with poor prognosis of sepsis.

ABSTRACT: The functional significance of extracellular Niemann-Pick disease type C2 protein (NPC2) is poorly defined. It is not known whether there is an association between plasma NPC2 and sepsis. Our exploratory, quantitative proteomic analysis showed a significant increase in the level of plasma NPC2 in moribund sepsis patients. Thus, we subsequently determined NPC2 concentration in plasma from healthy subjects, pneumonia patients and sepsis patients with comorbid pneumonia; and analyzed the association of plasma NPC2 with organ dysfunction and prognosis of sepsis patients. Our data shows that plasma NPC2 concentration was significantly higher in pneumonia and sepsis patients than healthy subjects, and was further increased in sepsis patients when the SOFA score reached 14. In addition, NPC2 concentration was significantly higher in patients that subsequently developed septic shock or died within 30 days. Moreover, NPC2 level showed the strongest association with the degree of renal dysfunction in sepsis patients. In moribund sepsis patients, however, NPC2 had highest correlation coefficient with indicators of coagulation anomaly. Based on these results, we conclude that the increase in plasma NPC2 in sepsis patients is associated with multiple organ failure, possibly results from a deficiency in renal clearance, and may serve as a prognostic marker for sepsis.

SUBMITTER: Bai Y

PROVIDER: S-EPMC7961030 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Increase in plasma Niemann-Pick disease type C2 protein is associated with poor prognosis of sepsis.

Bai Yu Y Yin Shuangyi S Gbordzor Vivian V Guo Yu Y Bai Qing Q Wang Shuaiwei S Wei Xiangyan X Chen Na N Zhang Yijie Y Li Wei W

Scientific reports 20210315 1

The functional significance of extracellular Niemann-Pick disease type C2 protein (NPC2) is poorly defined. It is not known whether there is an association between plasma NPC2 and sepsis. Our exploratory, quantitative proteomic analysis showed a significant increase in the level of plasma NPC2 in moribund sepsis patients. Thus, we subsequently determined NPC2 concentration in plasma from healthy subjects, pneumonia patients and sepsis patients with comorbid pneumonia; and analyzed the associatio ...[more]

PMID: 33723331

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Project description:Background and aimsHepatic cholesterol deposition drives inflammation and fibrosis in non-alcoholic steatohepatitis (NASH). The Niemann-Pick type C2 (NPC2) protein plays an important role in regulating intracellular cholesterol trafficking and homeostasis. We hypothesized that intravenous NPC2 supplementation reduces cholesterol accumulation, hepatic inflammation and fibrogenesis in a nutritional NASH rat model.MethodsRats were fed a high-fat, high-cholesterol (HFHC) diet for four weeks resulting in moderately severe NASH. Animals were treated with intravenous NPC2 or placebo twice weekly for either the last two weeks or the entire four weeks. End-points were liver/body- and spleen/body weight ratios, histopathological NASH scores, fibrosis, serum liver enzymes, cholesterol, lipoproteins, cytokines, and quantitative polymerase chain reaction derived hepatic gene expression related to cholesterol metabolism, inflammation, and fibrosis.ResultsHFHC rats developed hepatomegaly, non-fibrotic NASH histopathology, elevated liver enzymes, serum cholesterol, and pro-inflammatory cytokines. Their sterol regulatory element binding factor 2 (SREBF2) and low-density lipoprotein receptor (LDL-R) mRNAs were down-regulated compared with rats on standard chow. NPC2 did not improve liver weight, histopathology, levels of serum liver enzymes or pro-inflammatory tumor necrosis factor-α (TNFα), Interleukin (IL)-6, or IL-1β in HFHC rats. Two weeks of NPC2 treatment lowered hepatic TNFα and COL1A1 mRNA expression. However, this effect was ultimately reversed following additional two weeks of treatment. Four weeks NPC2 treatment of rats raised ATP-binding cassette A1 (ABCA1) and low-density lipoprotein receptor (LDLR) mRNAs in the liver, concurrent with a strong tendency towards higher serum high-density lipoprotein (HDL). Furthermore, the peroxisome proliferator activated receptor-ɣ (PPARG) gene expression was reduced.ConclusionsNPC2 proved inefficient at modifying robust hepatic NASH end-points in a HFHC NASH model. Nonetheless, our data suggest that hepatic ABCA1 expression and reverse cholesterol transport were upregulated by NPC2 treatment, thus presenting putative therapeutic effects in diseases associated with deregulated lipid metabolism.

Project description:Niemann-Pick Type C2 (NPC2) plays an important role in the regulation of intracellular cholesterol homeostasis via direct binding with free cholesterol. However, little is known about the significance of NPC2 in cancer. In this study, we have pinpointed the impact of various different cancers on NPC2 expression. A series of anti-NPC2 monoclonal antibodies (mAbs) with the IgG2a isotype were generated and peptide screening demonstrated that the reactive epitope were amino acid residues 31-40 of the human NPC2 protein. The specificity of these mAbs was confirmed by Western blotting using shRNA mediated knock-down of NPC2 in human SK-Hep1 cells. By immunohistochemical staining, NPC2 is expressed in normal kidney, liver, breast, colon, lung, esophageal, uterine cervical, pancreatic and stomach tissue. Strong expression of NPC2 was found in the distal and proximal convoluted tubule of kidney and the hepatocytes of liver. Normal esophageal, uterine cervical, pancreatic, stomach, breast, colon and lung tissue stained moderately to weakly. When compared to their normal tissue equivalents, NPC2 overexpression was observed in cancers of the breast, colon and lung. Regarding to breast cancer, NPC2 up-regulation is associated with estrogen receptor (-), progesterone receptor (-) and human epidermal growth factor receptor (+). On the other hand, NPC2 was found to be down-regulated in renal cell carcinoma, liver cirrhosis and hepatoma tissues. By antigen-capture enzyme immunoassay ELISA, the serum NPC2 is increased in patients with cirrhosis and liver cancer. According to western blot data, the change of glycosylated pattern of NPC2 in serum is associated with cirrhosis and liver cancer. To the best of our knowledge, this is the first comprehensive immunohistochemical and serological study investigating the expression of NPC2 in a variety of different human cancers. These novel monoclonal antibodies should help with elucidating the roles of NPC2 in tumor development, especially in liver and breast cancers.

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Increase in plasma Niemann-Pick disease type C2 protein is associated with poor prognosis of sepsis.

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Increase in plasma Niemann-Pick disease type C2 protein is associated with poor prognosis of sepsis.

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