Trimming the Fat: Acetyl‐CoA Carboxylase Inhibition for the Management of NAFLD

Imai, Norihiro; Cohen, David E.

doi:10.1002/hep.30206

Cited by 26 publications

(13 citation statements)

References 13 publications

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“…7A). Cytosolic malonyl-CoA produced by ACC1 is used primarily as substrate for fatty acid biosynthesis; in contrast, malonyl-CoA produced by ACC2 allosterically inhibits mitochondrial fatty acid transporter CPT1 (56). Reduction in ACC1 and ACC2 levels by MST3 knockdown is thus expected to reprogram hepatocyte metabolism, leading to reduced fatty acid synthesis and increased mitochondrial b-oxidation.…”

Section: Reduced Lipogenic Gene Expression and Acetyl-coenzyme A Carbmentioning

confidence: 99%

Protein kinase MST3 modulates lipid homeostasis in hepatocytes and correlates with nonalcoholic steatohepatitis in humans

et al. 2019

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Ectopic lipid storage in the liver is considered the main risk factor for nonalcoholic steatohepatitis (NASH). Understanding the molecular networks controlling hepatocellular lipid deposition is therefore essential for developing new strategies to effectively prevent and treat this complex disease. Here, we describe a new regulator of lipid partitioning in human hepatocytes: mammalian sterile 20‐like (MST) 3. We found that MST3 protein coats lipid droplets in mouse and human liver cells. Knockdown of MST3 attenuated lipid accumulation in human hepatocytes by stimulating β‐oxidation and triacylglycerol secretion while inhibiting fatty acid influx and lipid synthesis. We also observed that lipogenic gene expression and acetyl‐coenzyme A carboxylase protein abundance were reduced in MST3‐deficient hepatocytes, providing insight into the molecular mechanisms underlying the decreased lipid storage. Furthermore, MST3 expression was positively correlated with key features of NASH (i.e., hepatic lipid content, lobular inflammation, and hepatocellular ballooning) in human liver biopsies. In summary, our results reveal a role of MST3 in controlling the dynamic metabolic balance of liver lipid catabolism vs. lipid anabolism. Our findings highlight MST3 as a potential drug target for the prevention and treatment of NASH and related complex metabolic diseases.—Cansby, E., Kulkarni, N. M., Magnusson, E., Kurhe, Y., Amrutkar, M., Nerstedt, A., Ståhlman, M., Sihlbom, C., Marschall, H.‐U., Borén, J., Blüher, M., Mahlapuu, M. Protein kinase MST3 modulates lipid homeostasis in hepatocytes and correlates with nonalcoholic steatohepatitis in humans. FASEB J. 33, 9974–9989 (2019). http://www.fasebj.org

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Section: Reduced Lipogenic Gene Expression and Acetyl-coenzyme A Carbmentioning

confidence: 99%

Protein kinase MST3 modulates lipid homeostasis in hepatocytes and correlates with nonalcoholic steatohepatitis in humans

et al. 2019

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“…Low cellular energy causes activation of AMPK which inactivates both ACC isoforms, ACC-1 and ACC-2, resulting in reduced de novo lipogenesis and increased fatty acid oxidation [42]. Similarly, biotin supplementation in mice and rats has been reported to increase the active form of AMPK, which phosphorylates ACC-1 and ACC-2, resulting in decreases in the rate of lipid synthesis and increases in fatty acid oxidation rates [43,44].…”

Section: Resultsmentioning

confidence: 99%

Effects of Magnesium Biotinate Supplementation on Serum Insulin, Glucose, and Lipid Parameters Along with Gene Expressions of Intermediary Metabolism in Rats

Şahin

Orhan

Küçük

et al. 2020

Preprint

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Background: The objective of this work was to investigate the effects of a novel form of biotin (magnesium biotinate) at various levels on body weight, serum concentrations of glucose, insulin, cholesterol, and triglycerides, and liver expression of lipid metabolism-related genes such as SREBP-1c, FAS, AMPK-α1, ACC-1, ACC-2, PC, PCC and MCC in rats.Methods: A total of 42 male Sprague-Dawley rats were divided into six treatment groups and fed a standard diet-based egg white powdered diet supplemented with either commercial biotin (d-biotin) at 0.01, 1 or 100 mg/kg body weight or a novel form of biotin (magnesium biotinate) at 0.01, 1, or 100 mg/kg bodyweight for 35 days. The doses used at 0.01, 1 and 100 mg from each source represented a standard dietary dose (control), high dietary dose, and pharmacologic dose, respectively. Results: Bodyweight changes, feed intake, serum concentrations of glucose, insulin, creatine, and urea, and enzyme activities of ALT and AST were similar among treatments (P > 0.05). Serum total cholesterol and triglyceride concentrations of the rats decreased with biotin supplementation from both sources (P < 0.05). Concentrations were significantly lower with magnesium biotinate when comparing the 1 mg/kg dose groups (P < 0.05). Serum, liver, brain biotin concentrations, and liver cGMP contents were greater when rats were treated with magnesium biotinate versus d-biotin, particularly when comparing the 1 mg/kg and 100 mg/kg dose groups (P < 0.05). Both forms of biotin decreased the liver gene expression of SREBP‐1c and FAS and increased liver gene expression of AMPK-α1, ACC-1, ACC-2, PCC and MCC (P < 0.05). The magnitudes of responses were more emphasized with magnesium biotinate. Liver PC gene expression increased with biotin supplementation with no regard to dose or biotin form (P > 0.05).Conclusion: Results of the present work revealed that a new form of biotin, magnesium biotinate, compared with a commercial d-biotin, is more effective in reducing serum lipid concentrations and in regulating gene expressions of intermediary metabolism-related biomarkers.

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“…Silencing SCD1 results an increased accumulation of SFA over time by modulating SFA/ MUFA ratios that hinder acetyl-CoA carboxylases (ACC) activity through a well-known feedback mechanism resulting in a drop of malonyl-CoA that down-regulates carnitine-palmitoyl transferase (CPT) and in turn increases transport of acyl-CoA into mitochondria for β-oxidation [59]. This upregulated β-oxidation in turn increases the reaction rate of many of the steps decarboxylase; CPT, carnitine-palmitoyl transferase; Glu-6P, glucose 6-phospate; Glu-1P, glucose 1-phospate; Gal-6P, galactose 6-phospate; Gal-1P, galactose in the TCA cycle, thereby increasing flux throughout the pathway and resulting in higher accretion of TCA cycle intermediates over time, i.e.…”

Section: Integrative Metabolic Pathway Analysismentioning

confidence: 99%

Anopheles coluzzii stearoyl-CoA desaturase is essential for adult female survival and reproduction upon blood feeding

et al. 2021

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Vitellogenesis and oocyte maturation require anautogenous female Anopheles mosquitoes to obtain a bloodmeal from a vertebrate host. The bloodmeal is rich in proteins that are readily broken down into amino acids in the midgut lumen and absorbed by the midgut epithelial cells where they are converted into lipids and then transported to other tissues including ovaries. The stearoyl-CoA desaturase (SCD) plays a pivotal role in this process by converting saturated (SFAs) to unsaturated (UFAs) fatty acids; the latter being essential for maintaining cell membrane fluidity amongst other housekeeping functions. Here, we report the functional and phenotypic characterization of SCD1 in the malaria vector mosquito Anopheles coluzzii. We show that RNA interference (RNAi) silencing of SCD1 and administration of sterculic acid (SA), a small molecule inhibitor of SCD1, significantly impact on the survival and reproduction of female mosquitoes following blood feeding. Microscopic observations reveal that the mosquito thorax is quickly filled with blood, a phenomenon likely caused by the collapse of midgut epithelial cell membranes, and that epithelial cells are depleted of lipid droplets and oocytes fail to mature. Transcriptional profiling shows that genes involved in protein, lipid and carbohydrate metabolism and immunity-related genes are the most affected by SCD1 knock down (KD) in blood-fed mosquitoes. Metabolic profiling reveals that these mosquitoes exhibit increased amounts of saturated fatty acids and TCA cycle intermediates, highlighting the biochemical framework by which the SCD1 KD phenotype manifests as a result of a detrimental metabolic syndrome. Accumulation of SFAs is also the likely cause of the potent immune response observed in the absence of infection, which resembles an auto-inflammatory condition. These data provide insights into mosquito bloodmeal metabolism and lipid homeostasis and could inform efforts to develop novel interventions against mosquito-borne diseases.

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Trimming the Fat: Acetyl‐CoA Carboxylase Inhibition for the Management of NAFLD

Cited by 26 publications

References 13 publications

Protein kinase MST3 modulates lipid homeostasis in hepatocytes and correlates with nonalcoholic steatohepatitis in humans

Protein kinase MST3 modulates lipid homeostasis in hepatocytes and correlates with nonalcoholic steatohepatitis in humans

Effects of Magnesium Biotinate Supplementation on Serum Insulin, Glucose, and Lipid Parameters Along with Gene Expressions of Intermediary Metabolism in Rats

Anopheles coluzzii stearoyl-CoA desaturase is essential for adult female survival and reproduction upon blood feeding

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