Implication of Mitochondrial Coenzyme Q10 (Ubiquinone) in Alzheimer’s Disease *
Abhai Kumar, Debasis Bagchi in Antioxidants and Functional Foods for Neurodegenerative Disorders, 2021
The precursor of the quinone ring is only 4-hydroxybenzoic acid (4-HB), which is derived from tyrosine. Mevalonate pathway is the main route to synthesize the isoprenoid tail, which is also common to cholesterol biosynthesis. The initial part of the mevalonate pathway involves the condensation of three acetyl-CoA to form 3-hydroxy-3-methylglutaryl-CoA by HMG-CoA reductase, which is the main regulatory enzyme in cholesterol biosynthesis. Mevalonate is subsequently phosphorylated in two steps by mevalonate kinase (MVK) and phosphomevalonate kinase (PMVK). Then, decarboxylation of mevalonate pyrophosphate yields isopentenyl pyrophosphate (IPP), which is the precursor of farnesyl pyrophosphate (FPP) and the building block for the biosynthesis of dolichol and the side chain of CoQ. Isomerization of IPP gives dimethylallyl pyrophosphate (DMAPP), and FPP synthase utilizes IPP and DMAPP to make FPP with the intermediary formation of geranyl pyrophosphate (GPP). FPP is further converted into cholesterol, dolichols, and CoQ [6]. Decalyprenyl diphosphate synthase (DPS) is a heterotetramer consisting of two different proteins, namely, PDSS1 and PDSS2. DPS catalyzes the condensation of IPP and FPP to produce ten units of prenyldiphosphate (decaprenyl diphosphate). 4-Hydroxybenzoic acid-decaprenyl diphosphate transferase (encoded by CoQ2 gene in humans) catalyzes the condensation of PHB with the isoprenoid tail to yield CoQ10 [7,8].
Anredera cordifolia (Ten.) v. Steenis
Dilip Ghosh, Pulok K. Mukherjee in Natural Medicines, 2019
The anti-obesity effect of Anredera cordifolia, particularly the secondary metabolites apigenin and apigetrin, was studied further in silico. This study was conducted to investigate in silico interaction between apigenin and apigetrin with 3-hydroxy-3-methyl-glutayl-co-enzyme A (HMG Co-A) reductase, to find the most favourable binding site as well as to predict the binding mode. HMG Co-A reductase is the rate-controlling enzyme of the mevalonate pathway, which produces cholesterol and other isoprenoids. Results showed binding affinity and inhibition constants of R-mevalonate were Ei = −4.2 kcal/mol, Ki = 836.78 μM; apigenin Ei = −7.0 kcal/mol, Ki = 7.43 μM; apigetrin Ei = −5.9 kcal/mol, Ki = 47.53 μM; simvastatin Ei = −8.2 kcal/mol; Ki = 0.98 μM; atorvastatin Ei = −8.4 kcal/mol; Ki = 0.7 μM. Apigenin had a better binding interaction than apigetrin. This research indicated the potential of apigenin to be developed as an anticholesterol drug (Lestari et al. 2017).
Impact of Probiotics on Human Gut Microbiota and the Relationship with Obesity
Marcela Albuquerque Cavalcanti de Albuquerque, Alejandra de Moreno de LeBlanc, Jean Guy LeBlanc, Raquel Bedani in Lactic Acid Bacteria, 2020
Butyrate has been found to improve insulin sensitivity (Hartstra et al. 2015), to increase leptin gene expression by regulating food intake and body weight (Harris et al. 2012), and to possess obesity-related anti-inflammatory action by regulation of tight junction gene expression, increasing, consequently, intestinal barrier function (Brahe et al. 2013, Hartstra et al. 2015). Propionic acid also has a favourable effect on leptin gene expression reducing the intake of food and regulating weight gain (Xiong et al. 2004, Lin et al. 2012). Additionally, propionate is able to reduce cholesterol synthesis (Harris et al. 2012). Although acetate serves as a substrate for synthesis of cholesterol and has an influence on the synthesis of lipids in liver (Sanz et al. 2010), it has been demonstrated that acetic acid also has the ability to inhibit weight gain (Lin et al. 2012, Christiansen et al. 2018).
An update on synthetic high-density lipoprotein-like nanoparticles for cancer therapy
Published in Expert Review of Anticancer Therapy, 2019
Stephen E. Henrich, C. Shad Thaxton
Cholesterol homeostasis is maintained at the organismal level in vivo by the dynamic regulation of cholesterol synthesis, efflux, and influx. Because cholesterol is minimally soluble in water, it requires transport via amphiphilic carriers. These carriers are the five classes of lipoproteins mentioned in Section 2, which form colloidal suspensions in the blood [33]. LDL is the primary transporter of cholesterol from the liver to peripheral cells. Cholesterol is delivered by LDL to recipient cells via LDL receptor-mediated endocytosis [34]. HDL, by contrast, removes cholesterol from the periphery and delivers it back to the liver for excretion in the bile [35]. However, HDL, unlike LDL, is capable of both delivering and removing cholesterol from cells. HDL removes cholesterol from cells by binding to one of its three receptors, ABCA1, ABCG1, and SR-B1. However, SR-B1 is the only receptor through which HDL can both efflux and influx cholesterol [36]. Because of this, SR-B1 is frequently overexpressed in neoplastic cells and has been the most thoroughly investigated of the cholesterol efflux receptors in the context of cancer [37,38]. A comprehensive treatment of the crossover between HDL biology and cancer, and the respective roles of each of the HDL receptors can be found in a recent review article published by Ganjali et. al. [39].
An update on drug development for the treatment of nonalcoholic fatty liver disease – from ongoing clinical trials to future therapy
Published in Expert Review of Clinical Pharmacology, 2021
IBAT inhibitors are a new substance class that interrupts enterohepatic circulation of bile acids by inhibiting ileal bile acid transporter (IBAT). Phase 1 studies showed a decrease in serum FGF19 and thereby a reduced feedback regulation of bile acid synthesis. An increased bile acids synthesis led to a compensatory increase of cholesterol synthesis with higher expression of LDL receptor and decrease of LDL cholesterol in serum. The IBAT inhibitor Elobixibat achieved the primary endpoint of reduction of LDL-cholesterol in a phase 2 study (NCT04006145) but did not achieve therapeutic proof-of-concept for other key NASH measures (e.g. liver fat reduction by MRI-PDFF or reduction in liver transaminases) [28]. Therefore, further development of Elobixibat in NASH is currently not pursued, but the drug class remains an interesting pathophysiological target for NASH treatment.
Immune metabolism: a bridge of dendritic cells function
Published in International Reviews of Immunology, 2022
Yuting Sun, Liyu Zhou, Weikai Chen, Linhui Zhang, Hongbo Zeng, Yunxia Sun, Jun Long, Dongping Yuan
Cells increase intracellular cholesterol in two ways (Figure 3). Cholesterol is taken up through extracellular low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) [58], and synthesized in the ER [54]. Cholesterols can be ingested from serum LDL and VLDL, which are internalized through low-density lipoprotein receptor (LDLR) and very low-density lipoprotein receptor (VLDLR) on the cell surface. Cholesterol ester of LDL and VLDL is hydrolyzed in the lysosome and free cholesterol is released to the plasma membrane, which involves Niemann-Pick type C1 (NPC1) protein [58–61]. In addition, acetyl-CoA can be converted to cholesterol through mevalonate pathway including at least 20 enzymes [62]. All of the enzymes containing rate-limiting enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase in ER are regulated by the sterol regulatory element-binding proteins (SREBPs) transcription factor family [63]. Cholesterol derived from ER can be transported to raft or non-raft microdomains on the plasma membrane via the Golgi. However, when secreted proteins are blocked from being transferred from the ER, most of the cholesterol bypasses the Golgi apparatus and reaches the cell membrane [64].
Related Knowledge Centers
- Archaea
- Bacteria
- Eukaryote
- Metabolic Pathway
- Terpenoid
- Vitamin K
- Hmg-Coa Reductase
- Isopentenyl Pyrophosphate
- Dimethylallyl Pyrophosphate
- Cholesterol