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Inhibitors on Lipoprotein Lipase Transcriptase The effect of nucleoside/nucleotide reverse... JKCD September 2019, Vol. 9, No. 3 THE EFFECT OF NUCLEOSIDE/NUCLEOTIDE REVERSE TRANSCRIPTASE INHIBITORS AND PROTEASE INHIBITORS ON LIPOPROTEIN LIPASE Khawar Anwar1 , Sultan Zeb2, Abir Hussain 3, Ayub Jan4, Tahir S Pillay5 , Akbar Said Jan6 1Department of Bio-Chemistry, Shahida Islam Medical & Dental College, Lodhran 2Department of Anatomy, Northwest School of Medicine, Peshawar. 3Department of Community Dentistry, Frontier Medical & Dental College, Abbottabad. 4Public Health Student Abdul Wali Khan University, Mardan 5Departments of Chemical Pathology, Faculty of Health Sciences, University of Pretoria, Pretoria, S. Africa. 6Department of Anaesthesiology, Northwest School of Medicine, Peshawar. ABSTRACT In the treatment of HIV/AIDS, protease inhibitors (PIs) and nucleoside/nucleotide analog reverse transcriptase inhibitors (NRTIs) are the major components of highly active antiretroviral therapy (HAART). The side effects of these drugs include various metabolic disorders, including insulin resistance, dyslipidemia, and lipodystrophy. The precise mechanistic basis of these remains mostly unknown. Objectives :In this study, we aimed to understand the enzymatic activity of lipoprotein lipase (LPL) under the influence of NRTIs and PIs. Material and Methods: Chinese hamster ovary cells transfected with the human insulin receptor (CHO-IR) were used for the first time to study the effects of NRTIs and PIs on the synthesis and release of LPL. The high level of expression of insulin receptor facilitated sensitive detection of any alteration in the phosphorylation of signaling proteins as compared to 3T3-L1 adipocytes. LPL activity in the supernatant and cell lysate was measured using a colorimetric method em- ploying para-nitrophenyl butyrate(pNPB) as a substrate. The most commonly used ARVs were tested. These included four PIs and six NRTIs. Results :The results showed that NRTIs stavudine and emtricitabine significantly inhibited the LPL activity from the CHO-IR cells. PIs indinavir and nelfinavir were also found to decrease LPL activity extracellularly when added to the assay reaction in vitro.Similarly, nelfinavir and atazanavir sulfate inhibited the activity of the LPL from the CHO-IR cells after 16-hour treatment. This suggested that these drugs may interfere with the enzyme activity intracellularly either at the level of its synthesis or its transportation from the cytoplasm to the cell surface. Conclusion :This finding suggests that protease inhibitors may play a role in inhibiting lipopro- tein lipase activity in vivo, and may thereby induce metabolic disorders in HIV-positive patients being treated with protease inhibitors Key Word: Lipoprotein lipase, Nucleoside/nucleotide reverse transcriptase inhibitors,Protease inhibitors Correspondence: Introduction Dr. Khawer Anwar, Assistant Professor, Bio-Chemistry Department, Shahida Lipoprotein lipase (LPL) is a central enzyme Islam Medical and Dental College Lodhran in lipid metabolism and transport. It is produced in Email: [email protected] Contact: +92-334-1140700 numerous cell types, but the skeletal muscle and the Available Online 30-September 2019 at http://www.jkcd.edu.pk DOI: https://doi.org/10.33279/2307-3934.2019.9126 1 The effect of nucleoside/nucleotide reverse... JKCD September 2019, Vol. 9, No. 3 parenchyma of adipose tissue are the significant sites LPL release from cells is increased by both of synthesis and physiological actions. insulin and heparin in a dose and time-dependent manner. The mechanisms by which insulin and The physiological location of LPL-mediated hy- heparin release LPL from the cells are not precisely drolysis of lipoproteins is at the capillary endothelial known. Some researchers have observed that heparin cell, but functional LPL is first synthesized by the acts as a secretagogue, thereby suggesting that the parenchymal cells and then translocated to its site released LPL is at first present in intracellular secre- of action 1-3. tory vesicles, which fuse with the plasma membrane There are four main levels of regulation, depend- upon stimulation with heparin. Other data indicate ing upon the location of LPL synthesis in different that there is a heparin-binding site on the LPL dimer, tissues. These are at the transcriptional, posttran- which binds to the heparin sulphate-proteoglycan scriptional, translational, and post-translational extracellular matrix. Heparin treatment of cells shifts levels. These four levels are locally controlled by the plasma membrane-bound LPL by competition different factors in different tissues. This local con- with the HSP, resulting in the release of LPL into trol on LPL synthesis enables tissues to maintain a the cell culture medium 14-16. balance in lipid metabolism, and it also modulates Intracellular glucose levels also accelerate LPL other cellular functions and hormonal effects on the synthesis in adipocytes, and its boosting effect on local tissues 4. LPL is mainly associated with glycosylation of LPL plays an important role in lipid metabolism LPL, which is very important for the regular LPL and transport. It catalyzes the hydrolysis of Triacyl- enzymatic activity and its release. Glucose also glycerol (TAG) attached to circulating chylomicrons enhances the effects of insulin to increase LPL syn- and Very Low-Density Lipoprotein (VLDL). The thesis, but there is no evidence that glucose affects resulting reaction produces non-esterified fatty the transcriptional level (mRNA) of LPL synthesis, acids (NEFA) and 2-monoacylglycerol for tissue as observed with insulin 17,18. Different studies asso- utilization 3,5-7. NEFAs in white adipose tissue are ciate insulin resistance with decreased LPL activity, re-esterified for energy storage as TAG 5. Addition- hypertriglyceridaemia, elevated cholesterol and ally, fatty acids are oxidized to provide an energy chylomicronaemia19,20 source in the heart and to regulate thermogenesis in A recent study in insulin-resistant offspring brown adipose tissue 5. of type 2 diabetes parents revealed a link between Role of insulin, heparin, and glucose in lipo- insulin resistance and decreased mitochondrial con- protein lipase regulation tent, as evidenced by decreased mRNA and protein 21 As discussed above, the regulation of LPL syn- expression of LPL in muscle biopsies . Usually, thesis is essential for normal homeostasis of lipid free fatty acid delivery into skeletal muscle results in metabolism, and insulin is the primary regulator of mitochondrial biogenesis through activation of per- LPL synthesis in adipocytes and the translocation oxisome proliferator–activated receptor (PPAR)-δ. from there to the luminal domain of the endothelial The primary role of LPL here is to hydrolyze the cells. Generally insulin increases LPL activity but serum triglycerides and deliver free fatty acids to synthesis of LPL involves many steps including the muscle cells, as described above. LPL gene transcription, mRNA processing, trans- In many disorders such as diabetes, athero- port and translation, posttranslational modification sclerosis, and obesity, hypertriglyceridaemia is a (glycosylation) “activation” or “inactivation”, and characteristic feature. A well-known cause of genetic finally secretion 8-10. Insulin affects different steps hypertriglyceridaemia is the deficiency of lipoprotein of LPL synthesis in adipocytes such as during the lipase. In humans, type I hyperlipoproteinaemia, process of differentiation by enhancing gene tran- resulting from LPL deficiency, is a rare autosomal scription 11 while in fully differentiated adipocytes it recessive disease. It is characterized by low or no regulates LPL synthesis by increasing mRNA levels LPL activity resulting in hypertriglyceridaemia, de- and enzyme activity by both posttranscriptional and creased levels of HDL cholesterol, lipaemiaretinalis, post-translational modifications of LPL 11-13. and pancreatitis. There are three naturally occurring 2 The effect of nucleoside/nucleotide reverse... JKCD September 2019, Vol. 9, No. 3 mutations in LPL that affect lipid transport and activity in adipocytes and serum or plasma. Howev- metabolism and result in hypertriglyceridaemia and er, these methods are either expensive or laborious obesity in mice 22,23. and cumbersome. By contrast, an earlier method for assaying LPL in milk established that LPL-catalysed Disturbances in body fat distribution, dyslipid- hydrolysis of p-nitrophenyl butyrate (pNPB) could emia and insulin resistance, diabetes, and athero- be measured relatively easily and cheaply using the sclerosis in HIV patients are associated with ARV. appearance of p-nitrophenyl phosphate as an end However, the exact mechanisms of these changes product 34. have not been fully elucidated. HIV infection with acute and chronic effects of some antiretroviral drugs Preparation of CHO-IR cells for the assay of on regional fat distribution correlates with these side released lipoprotein lipase effects 24-26. It has already been reported that HIV CHO-IR cells were cultured and serum-starved, infection itself affects triglyceride metabolism and as described in sections 2.2.1 and 2.2.2. The cells lipoprotein lipase activity 27. were washed with PBS (2 ml) twice and left in an Hypertriglyceridaemia and impaired insulin additional fresh PBS (500 μl) containing insulin sensitivity can be observed even in HIV-negative (100ng/ml) (17nM) for one h at 37 °C in an incuba- subjects treated for short periods of time using pro- tor, to stimulate LPL activity.
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