Lipid Metabolism In Pathogenesis Research Articles

Quantitative Lipid Droplet Proteomics Reveals Mycobacterium tuberculosis Induced Alterations in Macrophage Response to Infection.

Growing evidence suggests the importance of lipid metabolism in pathogenesis of tuberculosis. Neutral lipids form the majority of lipids in a caseous granuloma, a pathology characteristic of tuberculosis. Cytosolic lipid droplets (LDs) of macrophages form the store house of these lipids and have been demonstrated to contribute to the inflammatory response to infection. The proteome of lipid droplets reflects the mechanisms of lipid metabolism active under a condition. However, infection induced changes in the proteome of these dynamic organelles remains elusive. Here, we employed quantitative proteomics to identify alterations induced upon infection with live Mycobacterium tuberculosis (Mtb) in comparison with heat killed bacilli or uninfected macrophages. We found increased abundance of proteins coupled with lipid metabolism, protein synthesis, and vesicular transport function in LDs upon infection with live Mtb. Using biochemical methods and microscopy, we validated ADP-ribosyltransferase (Arf)-like 8 (ARL8B) to be increased on the lipid droplet surface of live Mtb infected macrophages and that ARL8B is a bonafide LD protein. This study provides the first proteomic evidence that the dynamic responses to infection also encompass changes at the level of LDs. This information will be important in understanding how Mtb manipulates lipid metabolism and defense mechanisms of the host macrophage.

The expression and clinical effects of alpha-methylacyl-CoA racemase (AMACR/ P504S) as an immunohistochemical marker in malign pleural mesothelioma.

Alpha-methylacyl-CoA racemase (AMACR), an intracellular enzyme involved in lipid metabolism, has emerged as an immunohistochemical marker for many types of cancer. Recent studies about the role of lipid metabolism in pathogenesis of mesothelioma have brought up some positive results. This study was conducted to investigate AMACR expression in the diagnosis of malignant pleural mesothelioma (MPM) and the correlation of this marker with clinical characteristics and survival. The clinicopathologic characteristics and resection materials of 71 patients were reviewed retrospectively. AMACR expression was evaluated immunohistochemically. The correlations among AMACR expression, clinicopathologic factors, and survival were investigated. AMACR expression was detected in 42.3% of the study group. The specificity and sensitivity of AMACR immunostaining in detecting mesothelioma were 41.1% and 42.3%, respectively. AMACR-positive and negative groups were similar for age, sex, smoking history, tumor diameter, lymph node involvement, differentiation, T-N factor, and stage. Overall survival was not significantly different between the groups, either. The sensitivity of immunostaining was not high enough to use AMACR as a diagnostic tool in MPM. AMACR expression did not have a prognostic value in MPM, either.

Animal models for hepatitis C and related liver disease

Persistent infection with hepatitis C virus (HCV) is a major risk toward development of hepatocellular carcinoma (HCC). The elucidation of pathogenesis of HCV-associated liver disease is hampered by the absence of appropriate animal models: there has been no animal model for HCV infection/pathogenesis except for the chimpanzee. In contrast, a number of transgenic mouse lines carrying the cDNA of the HCV genome have been established and evaluated in the study of HCV pathogenesis. The studies using transgenic mouse models, in which the HCV proteins such as the core protein are expressed, indicate the direct pathogenicity of HCV, including oncogenic activities. HCV transgenic mouse models also show a close relationship between HCV and some hepatic and extrahepatic manifestations such as hepatic steatosis, insulin resistance or Sjögren's syndrome. A crucial role of hepatic steatosis and insulin resistance in the pathogenesis of liver disease in HCV infection has been demonstrated, implying hepatitis C to be a metabolic disease. Besides the data connecting liver fibrosis progression and the disturbance in lipid and glucose metabolisms in hepatitis C patients, a series of evidence was found showing the association between these two conditions and HCV infection, chiefly using transgenic mouse carrying the HCV genome. Furthermore, the persistent activation of peroxisome proliferator-activated receptor (PPAR)-alpha has recently been found, yielding dramatic changes in the lipid metabolism and oxidative stress overproduction in cooperation with the mitochondrial dysfunction. These results would provide a clue for further understanding of the role of lipid metabolism in pathogenesis of hepatitis C including liver injury and hepatocarcinogenesis.

Steatosis, liver injury, and hepatocarcinogenesis in hepatitis C viral infection

In addition to the link with development of hepatocellular carcinoma (HCC), hepatitis C virus (HCV) infection is associated with several hepatic and extrahepatic manifestations. A role of hepatic steatosis in the pathogenesis of chronic hepatitis C has been shown, implying hepatitis C as a metabolic disease. Furthermore, recent epidemiological studies have suggested a linkage between insulin resistance and chronic HCV infection. In addition to the data indicating the presence of lipid metabolism disturbance and insulin resistance in the cohort of chronic hepatitis C patients, we found evidence showing the association between these two conditions and HCV infection using mice transgenic for the HCV core gene. These mice develop HCC late in life after the phase of hepatic steatosis and insulin resistance. The nonappearance of both steatosis and HCC in HCV core gene transgenic mice that are null for the proteasome activator 28gamma implies a close relationship between lipid metabolism disturbance and hepatocarcinogenesis. Also, the core protein is shown to bind with retinoid X receptor (RXR)-alpha, resulting in the upregulation of some lipid metabolism enzymes, including cellular retinol binding protein II and acyl-CoA oxidase. In addition, the persistent activation of peroxisome proliferator activated receptor (PPAR)-alpha has recently been found in the liver of HCV core gene transgenic mice, yielding dramatic changes in lipid metabolism and hepatocyte proliferation, including HCC development. These results would provide a clue for further understanding of the role of lipid metabolism in pathogenesis of HCV infection, including liver injury and hepatocarcinogenesis.