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Molecular sport nutrition
Published in Adam P. Sharples, James P. Morton, Henning Wackerhage, Molecular Exercise Physiology, 2022
Mark Hearris, Nathan Hodson, Javier Gonzalez, James P. Morton
In addition to the enhanced ability to transport fatty acids into skeletal muscle and across the mitochondrial membrane, fat adaptation also increases the ability to store lipids within the muscle as IMTGs. In relation to timing, it is noteworthy that as little as two days of a high-fat diet has been shown to increase resting IMTG concentrations by 36% in endurance-trained cyclists (28). The increase in IMTG content appears to provide the main substrate responsible for the elevated rates of fat oxidation observed following fat adaptation, as inhibiting adipose tissue lipolysis (via the administration of a pharmacological lipolysis inhibitor, acipimox) does not significantly impact this response (28). The increase in IMTG concentrations following fat adaptation suggest an increase in lipid synthesis (the process of creating new lipids) above that of lipid degradation (the breakdown of lipids into their fatty acid constituents) during the rest periods between daily workouts. Whilst the increase in fatty acid transporters clearly plays a role in the ability to uptake fatty acids into skeletal muscle, the storage of fatty acids as triglycerides requires the attachment of fatty acids to the glycerol backbone. As this process requires the activity the enzymes glycerol-3-phosphate acyltransferase (GPAT) and diacylglycerol acyltransferase (DGAT) it seems plausible to consider that both enzymes may be upregulated in response to fat adaptation. Unfortunately, human studies to support this theory are currently lacking, although rodent studies have provided preliminary data that demonstrate increases in the mRNA expression of DGAT1 in skeletal muscle and the activity of GPAT within the liver, suggesting that both proteins are sensitive to alterations in fatty acid availability (29, 30). Clearly, more evidence is needed before definitive conclusions can be made in relation to how fat adaptation influences enzymes involved in lipid storage.
Modulation of Lipid Biosynthesis by Stress in Diatoms
Published in Gokare A. Ravishankar, Ranga Rao Ambati, Handbook of Algal Technologies and Phytochemicals, 2019
Bing Huang, Virginie Mimouni, Annick Morant-Manceau, Justine Marchand, Lionel Ulmann, Benoit Schoefs
DGAT enzymes play an important role in regulating TAG accumulation since they have been identified as the rate-limiting enzyme for oil accumulation in numerous oleaginous organisms (Lung and Weselake, 2006). Different types of DGAT can exist depending on the organism but two major isoforms, encoded by DGAT1 and DGAT2 genes, have been identified as responsible for the bulk of TAG synthesis in most organisms (Guihéneuf et al., 2011). In diatoms, only two DGAT genes were reported (Balamurugan et al., 2017; Dinamarca et al., 2017). Guihéneuf et al. (2011) characterized a DGAT1 gene in P. tricornutum. Its heterologous expression in neutral lipid-deficient yeast restored DGAT1 activity, resulting in lipid body formation in yeast cells. The recombinant yeast appeared to display a preference for incorporating saturated C16 and C18 fatty acids into TAG. Niu et al. (Niu et al., 2013) characterized a DGAT2 from P. tricornutum, and homologous overexpression triggered an increase in the neutral lipid content by 35% compared to the wild type with also a substantial increase (of 76%) in the proportion of PUFAs such as EPA. Moreover, the growth rate of transgenic microalgae remained similar. A similar experiment with another DGAT2 gene (DGAT2D) from P. tricornutum revealed a two-fold higher total lipid content and an incorporation of carbon into lipids more efficiently in transformants than in the WT while growing only 15% slower (Dinamarca et al., 2017). Flux analysis revealed that the increase in lipids was mainly achieved through pyruvate, suggesting that the conversion of pyruvate to acetyl-CoA would provide substrates for the TCA cycle, increasing simultaneously the production of precursors for ACCase toward FA biosynthesis (Dinamarca et al., 2017). Gong et al. (2013) identified a distinct DGAT2 gene in P. tricornutum (PtDGAT2B), the expression of which in TAG-deficient yeast strain completely restored TAG synthesis and lipid body formation while the proportion of unsaturated C16 and C18 fatty acids in yeast TAG was increased. Under nitrogen-replete conditions, PtDGAT2B was strongly upregulated before the onset of TAG accumulation, suggesting that this gene may be a contributor to TAG synthesis in nitrogen-replete cells.
Patent landscape for discovery of promising acyltransferase DGAT and MGAT inhibitors
Published in Expert Opinion on Therapeutic Patents, 2020
Vishal P. Zambre, Shamali M. Khamkar, Dnyaneshwar D. Gavhane, Sagar C. Khedkar, Monali R. Chavan, Madhuri M. Pandey, Sonali B. Sanap, Rajesh B. Patil, Sanjay D. Sawant
In the G-3-P pathway the first step is acylation of G-3-P with a fatty acyl CoA followed by acylation and dephosphorylation to obtain DAG. DAG is further converted to TAG by DGAT. DGAT enzyme exists in its two isoforms, i.e. DGAT1 and DGAT2. Both the enzymes have a distinct gene family. A detailed description on the role of DGAT1 and DGAT2 enzymes in triacylglycerol metabolism [7] and in cardiac metabolism and function [8] has been discussed recently. Experiments conducted on mice showed reduced adiposity in DGAT1 deficient mice and these mice were found to be viable with normal life span. Whereas, in DGAT2 deficient mice, it was found that they are lipopenic and die soon after birth [9]. In DGAT1-deficient mice obesity was not observed even after feeding TAG rich diet. In contrast, DGAT1 overexpressed mice were found to be obese when fed with TAG rich diet [10].
Obesity medications in development
Published in Expert Opinion on Investigational Drugs, 2020
Candida J. Rebello, Frank L. Greenway
Dietary triacylglycerol (TAG) is cleaved by lipases in the lumen of the gut to monoacylglycerol and free fatty acids which are taken up by the intestinal epithelial cells and re-esterified into TAG inside the epithelial cells. The TAG assembled in enterocytes is then incorporated into chylomicrons and enter the lymphatic system. Diacylglycerol acyltransferase 1 (DGAT1) plays a key role in the absorption of dietary fat as it catalyzes the final step in the biosynthesis of TAG [59] DGAT1 is most highly expressed in the small intestine and adipose tissue and the deletion of DGAT1 or inhibition of DGAT1 in rodents reduces body weight and adiposity, increases the secretion of GLP-1 and PYY, and slows gastric emptying [60–64]. Animal studies suggest that DGAT1 inhibition has therapeutic potential in the treatment of obesity.
Sulfur mustard analog 2-chloroethyl ethyl sulfide increases triglycerides by activating DGAT1-dependent biogenesis and inhibiting PGC1ɑ-dependent fat catabolism in immortalized human bronchial epithelial cells
Published in Toxicology Mechanisms and Methods, 2023
Feng Ye, Qinya Zeng, Guorong Dan, Yuanpeng Zhao, Wenpei Yu, Jin Cheng, Mingliang Chen, Bin Wang, Jiqing Zhao, Yan Sai, Zhongmin Zou
The two DGAT isoforms DGAT1 and DGAT2 have partially redundant functions in TG synthesis. In the present study, DGAT1 was increased in CEES-injured cells, and application of a DGAT1 inhibitor potently blocked TG biogenesis, indicating the TG increase induced by CEES required DGAT1. Possible mechanisms of DGAT1 increase could be autophagy activation and/or cell proliferation blockage, which could increase transcription factors such as C/EBPɑ or PPARγ binding to the DGAT1 promoter region to induce expression (Yen et al. 2008; Nguyen et al. 2017). In these conditions, the increased DGAT1 facilitated storage of excess fatty acids to prevent lipotoxicity.