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Rashid R.,University of Punjab | Ameer F.,University of Punjab | Kalbacher H.,University of Tubingen | Scandiuzzi L.,300 Morris Park Avenue | Zaidi N.,University of Punjab
Clinica Chimica Acta | Year: 2015

Human cells can acquire cholesterol from the circulation but also have the ability to synthesize it via de novo cholesterogenesis (DC). Cholesterol absorption and de novo cholesterogenesis are the key processes that modulate cholesterol homeostasis in the human body. The endogenous biosynthesis of cholesterol substantially contributes to the whole-body cholesterol pool. Additionally, dysregulation of this pathway is associated with diverse medical conditions. The present review focuses on our current understanding of the cholesterogenic pathway and the various different factors regulating this pathway. It also highlights dysregulation of this pathway in various physiological and pathological conditions including cardiovascular diseases, type II diabetes, obesity and viral infections. © 2015 Elsevier B.V. Source


Usman H.,University of Punjab | Ameer F.,University of Punjab | Munir R.,University of Punjab | Iqbal A.,University of Punjab | And 4 more authors.
Clinica Chimica Acta | Year: 2016

Background: Different types of cancer cells are previously shown to accumulate intracellular cholesterol. However, the data on intracellular cholesterol levels in leukemia cells provide contradictory evidence. Various previous works indicate either increase, decrease or no difference in total cholesterol levels between leukemia cells and healthy peripheral blood mononuclear cells (PBMCs). Methods: We studied the intracellular cholesterol levels in acute myeloid leukemia (AML) and acute lymphocytic leukemia (ALL) cells and compared with that in PBMCs from the healthy subjects. Results: We observed that the PBMCs from AML (n = 7) and ALL (n = 7) patients displayed significantly lower intracellular levels of total cholesterol in comparison to PBMCs from the healthy subjects (n = 26). Consistent with the patient data the ALL (CCRF-CEM and MOLT-3) and AML (KG-1 and THP-1) cell lines also displayed significantly lower intracellular levels of total cholesterol. We confirmed this observation using multiple methodological approaches. Both ALL and AML cell lines also displayed significantly lower levels of free cholesterol and cholesteryl ester contents in comparison to normal hematopoietic cells. We observed that >. 90% of the total cholesterol in leukemia cells as well as in normal PBMCs was present in the form of cholesteryl esters. It was also observed that the lower levels of cholesterol in leukemia cells are not affected by exogenous cholesterol availability. Conclusions: Present study provides convincing evidence to prove that the cellular free cholesterol and cholesteryl ester content is significantly reduced in leukemia cells in comparison to normal hematopoietic cells in circulation. Moreover, it was shown that the lower levels of cholesterol in leukemia cells are not affected by exogenous cholesterol availability. © 2015 Elsevier B.V.. Source


Ameer F.,University of Punjab | Scandiuzzi L.,300 Morris Park Avenue | Hasnain S.,University of Punjab | Kalbacher H.,University of Tubingen | Zaidi N.,University of Punjab
Metabolism: Clinical and Experimental | Year: 2014

Background De novo lipogenesis (DNL) is a complex and highly regulated metabolic pathway. In normal conditions DNL converts excess carbohydrate into fatty acids that are then esterified to storage triacylglycerols (TGs). These TGs could later provide energy via β-oxidation. In human body this pathway is primarily active in liver and adipose tissue. However, it is considered to be a minor contributor to the serum lipid homeostasis. Deregulations in the lipogenic pathway are associated with diverse pathological conditions. Scope of review The present review focuses on our current understanding of the lipogenic pathway with special reference to the causes and consequences of aberrant DNL. Major conclusions The deregulation of DNL in the major lipogenic tissues of the human body is often observed in various metabolic anomalies - including obesity, non-alcoholic fatty liver disease and metabolic syndrome. In addition to that de novo lipogenesis is reported to be exacerbated in cancer tissues, virus infected cells etc. These observations suggest that inhibitors of the DNL pathway might serve as therapeutically significant compounds. The effectiveness of these inhibitors in treatment of cancer and obesity has been suggested by previous works. General significance De novo lipogenesis - which is an intricate and highly regulated pathway - can lead to adverse metabolic consequences when deregulated. Therapeutic targeting of this pathway may open a new window of opportunity for combating various lipogenesis-driven pathological conditions - including obesity, cancer and certain viral infections. © 2014 Elsevier Inc. Source


Ilker Sen K.,300 Morris Park Avenue | Wu H.,Yeshiva University | Backer J.M.,Yeshiva University | Gerfen G.J.,300 Morris Park Avenue
Biochemistry | Year: 2010

Regulation of the class IA PI 3-kinase involves inhibition and stabilization of the catalytic subunit (p110) by the regulatory subunit (p85). Regulation is achieved by two major contacts: a stable interface involving the adapter-binding domain (ABD) of p110 and the inter-SH2 (iSH2) domain of p85 and a regulatory interaction between the N-terminal SH2 (nSH2) domain of p85 and the helical domain of p110. In the present study, we have examined the relative orientation of the nSH2 and iSH2 of p85α using site-directed spin labeling and pulsed EPR. Surprisingly, both distance measurements and distance distributions suggest that the nSH2 domain is highly disordered relative to the iSH2 domain. Molecular modeling based on EPR distance restraints suggests that the nSH2 domain moves in a hinge-like manner, sampling a torus space around the proximal end of the iSH2 domain. These data have important implications for the mechanism by which p85/p110 dimers are regulated by phosphopeptides. © 2010 American Chemical Society. Source


Iqbal A.,University of Punjab | Zaid M.,University of Punjab | Munir R.,University of Punjab | Usman H.,University of Punjab | And 4 more authors.
Clinica Chimica Acta | Year: 2016

Numerous studies have reported alterations in the plasma lipid profiles of leukemia patients. However, there are several inconsistencies in these reports. The present review highlights and compiles findings from different research groups regarding association of plasma lipoprotein levels with the risk of developing leukemia. We have also discussed the clinical significance of plasma lipid profiles in management of leukemia. Furthermore, the potential role of plasma lipids in promoting leukemogenesis is also highlighted. © 2015. Source

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