ABC Transporters, Organic Solute Carriers and Drug Metabolising Enzymes in Bile Duct Epithelial Cells
Gianfranco Alpini, Domenico Alvaro, Marco Marzioni, Gene LeSage, Nicholas LaRusso in The Pathophysiology of Biliary Epithelia, 2020
The ileal apical sodium-dependent bile salt transporter ASBT is expressed in the apical domain of cholangiocytes. The ASBT gene is transcriptionally regulated by HNF1a and PPARa. PPARa is a member of the peroxisomal proliferator activator receptor family. Inflammation increases PPARγ and this may interfere with PPARa binding, resulting in a down-regulation of ASBT expression.56 This occurs in the ileum. Whether this also occurs in bile duct epithelium needs to be studied. Down-regulation of ASBT in cholangiocytes would decrease the intrahepatic cycling of bile salts and, as a consequence, reduce the bile acid flux through hepatocytes. This may be an adaptive response in liver disease but this would occur at the cost of reducing the bile acid-dependent bile flow.
Mechanisms of action
Fazal-I-Akbar Danish, Ahmed Ehsan Rabbani in Pharmacology in 7 Days for Medical Students, 2018
Fenofibrate is a prodrug. It is converted to an active metabolite ‘fenofibric acid’ which is responsible for the triglyceride-lowering effect of the drug. Fenofibric acid, once formed, attaches to its receptor: peroxisome proliferator-activated receptor-alpha (PPAR-α). The activated receptor then binds to peroxisome proliferator response elements located in various gene promoters. These elements increase the expression of genes encoding for lipoprotein lipase. This enzyme is primarily found on the surface of endothelial cells. Its main function is to clip off free fatty acids from within the lipoprotein complexes so that the same can be taken up into the cells. This leads to depletion of triglycerides (3 × fatty acids + glycerol) from the lipoprotein complexes. Increased expression of lipoprotein lipase means increased clearance of triglyceride-rich lipoproteins from the circulation leading to a fall in triglyceride levels. This also in turn leads to decreased cholesterol biosynthesis in the liver.
Respiratory System
Pritam S. Sahota, James A. Popp, Jerry F. Hardisty, Chirukandath Gopinath, Page R. Bouchard in Toxicologic Pathology, 2018
With some orally delivered drugs, multifocal foamy macrophage aggregates appear scattered throughout the parenchyma. This effect, which often becomes more evident in the 2-year oncogenicity studies, has been seen in rats with peroxisome proliferator-activated receptor alpha (PPARα) agonists such as clofibrate and nafenopin, a PPARδ agonist, a p38 kinase inhibitor, and an iNOS inhibitor (Fringes et al. 1988a,b,c). These compounds do not have a cationic amphiphilic drug (CAD)-like structure; hence, the lesions were not consistent with PLO (discussed later). Similar changes were not seen in the corresponding mouse studies or the 9-month dog or nonhuman primate studies. The macrophages were not associated with any other inflammatory cell infiltration.
Protective effect of Qingluotongbi formula against Tripterygium wilfordii induced liver injury in mice by improving fatty acid β-oxidation and mitochondrial biosynthesis
Published in Pharmaceutical Biology, 2023
Jie Zhou, Ming Li, Zhichao Yu, Changqing Li, Lingling Zhou, Xueping Zhou
Transcriptional regulation is an important way to regulate metabolic processes (Desvergne et al. 2006). Peroxisome proliferator-activated receptor alpha (PPARα), a member of nuclear receptor superfamily, is the master regulator of energy metabolism and lipid catabolism in the liver (Kersten and Stienstra 2017). Previous studies showed that the suppression of PPARα is linked to the hepatotoxic mechanisms of Tripterygium glycosides tablets and Tripterygium wilfordii tablets, two preparations of TW (Dai et al. 2022). PPARα activation can alleviate triptolide-induced liver injury in mice (Hu et al. 2019). The transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) controls multiple hepatic metabolic pathways (Duan et al. 2022), and acts as a coactivator of PPARα to coordinately regulate the transcription of genes related to fatty acid oxidation and mitochondrial biogenesis (Vega et al. 2000). PPARα/PGC-1α pathway plays a central role in the regulation of cellular metabolism (Cheng et al. 2018). The activation of PPARα/PGC-1α can improve mitochondrial function (Kelly and Scarpulla 2004) and reduce lipotoxicity by enhancing lipid metabolism (Kim et al. 2022). We therefore speculate that the hepatic protective effect of QLT is probably related to the PPARα/PGC-1α pathway.
Current pharmacotherapy for the treatment of dyslipidemia associated with HIV infection
Published in Expert Opinion on Pharmacotherapy, 2019
Anna Gebhardt, Carl J. Fichtenbaum
One of the hallmarks of untreated HIV infection is hypertriglyceridemia. Initial potent antiretroviral therapy options were associated with very elevated levels of triglycerides. Hypertriglyceridemia may be associated with an atherogenic phenotype, and thus, treatment has been tried to reduce ASCVD risk and MACE endpoints. Fibrates work by activating peroxisome proliferator-activated receptor alpha (PPARα) lowering cholesterol by limiting substrate availability in the liver for TG synthesis, inhibiting their release and stimulating lipoprotein lipase thereby increasing TG clearance [88]. Gemfibrozil was effective in lowering hypertriglyceridemia induced by PIs in a randomized controlled trial of 37 participants with a 1.22 mmol/L decrease in triglycerides and few adverse effects or drug interactions [89]. In a retrospective study of clinical effectiveness in PWH gemfibrozil lowered TG 80 mg/dL, on average, whereas fenofibrate lowered TG 49 mg/dL [84]. Fenofibrate decreased TG by a median of 118 mg/dL in 87 PWH after 12 weeks [46]. Combination therapy with Pravastatin and fenofibrate for 36 weeks lowered TG by a median of 93 mg/dL [46]. In general, fibrates have been safe in PWH with few adverse events. Clinical trials of fibrates in the general population demonstrate reduction in ASCVD risk and mortality in one trial but most studies did not confirm this benefit [88]. Recent guidelines recommend that if TG>500 mg/dL initial management should begin with statins, and if those fail, fibrates can be added largely to avoid pancreatitis [39].
Targeting apoC-III and ANGPTL3 in the treatment of hypertriglyceridemia
Published in Expert Review of Cardiovascular Therapy, 2020
N.S. Nurmohamed, G.M. Dallinga – Thie, E.S.G. Stroes
In HTG, the treatment consists of two goals: reduce residual CVD risk and prevent acute pancreatitis; the latter is particularly important in severe HTG. During the last decades, multiple pharmacological strategies have been explored to effectively lower TG levels. Statins are the first choice of treatment to lower CVD risk in all hyperlipidemias, resulting in a reduction of plasma TG levels by 10–20% [20]. Fibrates currently are the most potent TG-lowering agents, achieving a TG lowering up to 50%, depending on baseline TG levels [20]. Large randomized clinical trials (RCT) have shown at best a modest effect of fibrates on CVD risk, evident in post hoc analyses of patients with elevated TG levels or when used without concomitant statin use [21–26]. Classic fibrates can also be associated with adverse effects regarding liver and renal function [27]. Currently, pemafibrate, a selective fibrate targeting peroxisome proliferator-activated receptor alpha (PPARα) with a more favorable side-effect profile, has entered a phase III outcomes study [28]. Its safety and efficacy was already extensively evaluated [29–32], whereas the PROMINENT trial will now provide results on CVD outcomes in primary prevention patients with diabetes [33].
Related Knowledge Centers
- Arachidonic Acid
- Nuclear Receptor
- Peroxisome
- Carcinogen
- Liver
- Transcription Factor
- Gene
- Peroxisome Proliferator-Activated Receptor Delta
- Peroxisome Proliferator-Activated Receptor Gamma
- Peroxisome Proliferator-Activated Receptor