Fatty Liver Disease
David Heber, Zhaoping Li in Primary Care Nutrition, 2017
Continuous fructose ingestion may impose a metabolic burden on the liver through the induction of fructokinase and fatty acid synthase. In the liver, fructose is metabolized to fructose-1-phosphate by fructokinase, which consumes ATP (Lim et al. 2010; Lustig 2010). As a consequence, a massive incorporation of fructose into liver metabolism can lead to high levels of metabolic stress via ATP depletion. In an experimental study in the rat (Koo et al. 2008), it was shown that fructose-induced fructokinase hyperexpression in the liver can be reduced (by 0.6-fold) by the hydroxymethyl-glutaryl-coenzyme A reductase inhibitor atorvastatin. Of note, clinical studies have shown that atorvastatin can improve liver injury in NAFLD patients with hyperlipidemia (Teff et al. 2004; Lê and Tappy 2006). Fatty acid synthase catalyzes the last step in the fatty acid biosynthetic pathway and is a key determinant of the maximal capacity of the liver to synthesize fatty acids by de novo lipogenesis (D’Angelo et al. 2005). In a clinical study, increased fructose consumption in patients with NAFLD was associated with hyperexpression of hepatic mRNA for fatty acid synthase, suggesting that this molecular derangement could play a crucial role in fructose-induced fatty liver infiltration (Ackerman et al. 2005).
Developmental Aspects of the Alveolar Epithelium and the Pulmonary Surfactant System
Jacques R. Bourbon in Pulmonary Surfactant: Biochemical, Functional, Regulatory, and Clinical Concepts, 2019
In addition to the activity of their respective biosynthetic pathways, the synthesis of surfactant phospholipids depends upon the availability of precursors for the synthesis of phosphatidic acid: fatty acids and substrates from the glycolytic pathway. The requirement for endogenous pulmonary fatty acid production in the prenatal period was discussed in chapter 3, Section IV.D. For instance, Patterson and co-workers166 have demonstrated that DSPC biosynthesis in fetal rat lung was dependent upon de novo palmitate supply. Fatty acid biosynthesis in developing fetal lung has been reviewed recently.167 In brief, an enhanced rate of fatty acid synthesis168–170 has been correlated with an increase in activity of fatty acid synthase, the enzyme which catalyzes the final steps in fatty acid synthesis. This increase has been reported during the last gestational days in the rabbit170 and rat171 fetus. Somewhat discrepant data have been reported regarding acetyl-CoA carboxylase activity. In the fetal rat, the latter was reported to peak close to term in two studies168,172 and to decline in another,171 while no change was observed in the fetal rabbit.173 A modest and transient postnatal increase of ATP-citrate lyase was observed in rat lung.172
Phosphatidate Phosphohydrolase in Plants and Microorganisms
David N. Brindley, John R. Sabine in Phosphatidate Phosphohydrolase, 2017
The high levels of polyunsaturated fatty acids in algal and plant membranes have already been mentioned. This fact makes the activity of the various aerobic desaturases particularly relevant although we know much less about these enzymes than about, for example, fatty acid synthase. The general process of fatty acid synthesis in plants (Figure 3) involves de novo synthesis of palmitate by fatty acid synthase, elongation to stearate, and Δ9-desaturation to oleate. These processes involve generally water-soluble acyl-ACPs (acyl-acyl carrier proteins). Further desaturation at the 18C level utilizes complex lipids as substrates.10 The generation of palmitate and oleate is a general property of a chloroplastic type II synthetase, a specific β-ketoacyl ACP synthetase,11 and a Δ9-desaturase.12 Further modifications of the acyl chains can take place within the plastid (desaturation) or in the extra-chloroplastic compartment. Indirect evidence implies that formation of trans-Δ3-hexadecenoic acid takes place while palmitate is esterified to the sn-2 position of phosphatidylglycerol while hexadecatrienoate synthesis is likely to occur while in the intact monogalactosyldiacylglycerol molecule.13
FASN Targeted by miR-497-5p Regulates Cell Behaviors in Cervical Cancer
Published in Nutrition and Cancer, 2022
Haiyan Zhang, Runmei Wang, Xuerui Tang, Jun Li, Jie Li, Mingxin Wang
Fatty acid (FA) is a major component of energy metabolism and a basic component of biofilm signal transduction network (7). Fatty acid synthase (FASN) is the main enzyme involved in FA synthesis (8). It has been illustrated to be vital in a variety of cancers (9, 10). For example, FASN is highly expressed in ovarian cancer and activates invasion and epithelial-mesenchymal transition (EMT) in cancer cells (11). In non-small cell lung cancer, FASN is markedly upregulated and miR-320 can inhibit cell proliferation, migration and invasion by degenerating FASN (12). Moreover, FASN is also associated with survival rate in bladder cancer patients, and PKM2 downregulating can inhibit transcriptional activation of FASN in bladder cancer (13). However, specific molecular mechanism of FASN in CC remains unknown.
Acetyl-CoA carboxylase (ACC) as a therapeutic target for metabolic syndrome and recent developments in ACC1/2 inhibitors
Published in Expert Opinion on Investigational Drugs, 2019
Leyuan Chen, Yuqing Duan, Huiqiang Wei, Hongxin Ning, Changfen Bi, Ying Zhao, Yong Qin, Yiliang Li
The structure of most eukaryotic ACCs is a polypeptide containing three major domains, biotin carboxylase (BC), biotin-containing carboxyl carrier protein (BCCP), and carboxyltransferase (CT). In most prokaryotic organisms, ACC is an enzyme complex comprised of multiple subunits. There are two isoforms of ACC found in mammals. One is ACC1 (ACCα, 265 kDa) encoded by ACACA gene on chromosome 17q12, and the other is ACC2 (ACCβ, 275 kDa) encoded by ACACB gene on chromosome 12q23 [8–11]. In mammals, ACC1 and ACC2 are highly conserved. The main difference is that ACC2 is a mitochondria protein directed by its hydrophobic N-terminal leader sequence to the mitochondrial membrane, while ACC1 is a cytoplasmic protein [12]. In liver and adipose tissue, malonyl-CoA produced by ACC1 acts as a fatty acid synthesis unit, and further extends the carbon chain to form long-chain fatty acids under the action of fatty acid synthase. ACC2 is mainly expressed in tissues such as heart and skeletal muscle, and its catalyzed production of malonyl-CoA is an inhibitor of CPT-1 (Figure 1) [13]. Due to their different distributions, selective inhibition of ACC1 or AAC2 may bring different physiological changes [11].
Clostridioides difficile: innovations in target discovery and potential for therapeutic success
Published in Expert Opinion on Therapeutic Targets, 2021
Tanya M Monaghan, Anna M Seekatz, Benjamin H Mullish, Claudia C. E. R Moore-Gillon, Lisa F. Dawson, Ammar Ahmed, Dina Kao, Weng C Chan
Fatty acids play a crucial role in the maintenance of the integrity of bacterial cell membranes, and their biosynthesis, as part of the non-mammalian type II fatty acid synthase (FASII) pathway, is mediated by a multitude of interlinked acyl carrier proteins (ACPs) in the cytoplasm [61,62]. Substrates of this pathway are bound to ACPs such as FabD, FabF and FabG, and undergo a series of reactions to extend their acyl chains; each elongation cycle is culminated by reduction, which is catalyzed by an enoyl-acyl carrier protein reductase. These enzymes thus serve as suitable antimicrobial targets, an example of which is isoniazid, an antibiotic used in treating Mycobacterium tuberculosis, and one which functions by inhibiting the reductase FabI [63]. Since bacterial species utilize specifically distinct enoyl-ACP reductases, its inhibition additionally provides a selective antimicrobial target. For instance, triclosan, another known FabI inhibitor, does not inhibit reductases such as FabK and FabV [64,65]. Although not as extensively studied as FabI, FabK has previously been reported as the sole reductase present in Streptococcus pneumoniae [66], and this has led to the identification of FabK inhibitors [67], including compounds derived from phenylimidazole [68].
Related Knowledge Centers
- Enzyme
- Fatty Acid Synthesis
- Palmitic Acid
- Peptide
- Protein
- Gene
- Substrate
- Saturated Fat
- Acetyl-Coa
- Malonyl-Coa