Acetoacetyl-CoA synthetase, a ketone body-utilizing enzyme, is controlled by SREBP-2 and affects serum cholesterol levels

Hasegawa, Shinya; Noda, Kazuki; A, Maeda; Matsuoka, Makoto; Yamasaki, Masahiro; Fukui, Tetsuya

doi:10.1016/j.ymgme.2012.08.017

Cited by 47 publications

(43 citation statements)

References 22 publications

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“…We hypothesized that substituting the KE for a portion of carbohydrate calories in the diet would reduce the amount of available acetyl-CoA for synthesis of steroids and fats in the liver. Acetoacetyl-CoA synthase (AACS) can also facilitate incorporation of ketones into lipogenesis [21] as indicated in Fig. 2, but this process is strongly controlled by insulin and feeding [22,23].…”

Section: Discussionmentioning

confidence: 99%

An Ester of β‐Hydroxybutyrate Regulates Cholesterol Biosynthesis in Rats and a Cholesterol Biomarker in Humans

Kemper

Srivastava

King

et al. 2015

Lipids

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In response to carbohydrate deprivation or prolonged fasting the ketone bodies, β-hydroxybutyrate (βHB) and acetoacetate (AcAc), are produced from the incomplete β-oxidation of fatty acids in the liver. Neither βHB nor AcAc are well utilized for synthesis of sterols or fatty acids in human or rat liver. To study the effects of ketones on cholesterol homeostasis a novel βHB ester (KE) ((R)-3-hydroxybutyl (R)-3-hydroxybutyrate) was synthesized and given orally to rats and humans as a partial dietary carbohydrate replacement. Rats maintained on a diet containing 30-energy % as KE with a concomitant reduction in carbohydrate had lower plasma cholesterol and mevalonate (-40 and -27 %, respectively) and in the liver had lower levels of the mevalonate precursors acetoacetyl-CoA and HMG-CoA (-33 and -54 %) compared to controls. Whole liver and membrane LDL-R as well as SREBP-2 protein levels were higher (+24, +67, and +91 %, respectively). When formulated into a beverage for human consumption subjects consuming a KE drink (30-energy %) had elevated plasma βHB which correlated with decreased mevalonate, a liver cholesterol synthesis biomarker. Partial replacement of dietary carbohydrate with KE induced ketosis and altered cholesterol homeostasis in rats. In healthy individuals an elevated plasma βHB correlated with lower plasma mevalonate.

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Section: Discussionmentioning

confidence: 99%

An Ester of β‐Hydroxybutyrate Regulates Cholesterol Biosynthesis in Rats and a Cholesterol Biomarker in Humans

Kemper

Srivastava

King

et al. 2015

Lipids

View full text Add to dashboard Cite

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“…The dynamic role of cytoplasmic ketone metabolism has been suggested in primary mouse embryonic neurons and in 3T3-L1 derived-adipocytes, as AACS knockdown impaired differentiation of each cell type (Hasegawa et al, 2012a; Hasegawa et al, 2012b). Knockdown of AACS in mice in vivo decreased serum cholesterol (Hasegawa et al, 2012c). SREBP-2, a master transcriptional regulator of cholesterol biosynthesis, and peroxisome proliferator activated receptor (PPAR)-γ are AACS transcriptional activators, and regulate its transcription during neurite development and in the liver (Aguilo et al, 2010; Hasegawa et al, 2012c).…”

Section: Non-oxidative Metabolic Fates Of Ketone Bodiesmentioning

confidence: 99%

“…Knockdown of AACS in mice in vivo decreased serum cholesterol (Hasegawa et al, 2012c). SREBP-2, a master transcriptional regulator of cholesterol biosynthesis, and peroxisome proliferator activated receptor (PPAR)-γ are AACS transcriptional activators, and regulate its transcription during neurite development and in the liver (Aguilo et al, 2010; Hasegawa et al, 2012c). Taken together, cytoplasmic ketone body metabolism may be important in select conditions or disease natural histories, but are inadequate to dispose of liver derived ketone bodies, as massive hyperketonemia occurs in the setting of selective impairment of the primary oxidative fate via loss of function mutations to SCOT (Berry et al, 2001; Cotter et al, 2011).…”

Section: Non-oxidative Metabolic Fates Of Ketone Bodiesmentioning

confidence: 99%

Multi-dimensional Roles of Ketone Bodies in Fuel Metabolism, Signaling, and Therapeutics

2017

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Ketone body metabolism is a central node in physiological homeostasis. In this review, we discuss how ketones serve discrete fine-tuning metabolic roles that optimize organ and organism performance in varying nutrient states, and protect from inflammation and injury in multiple organ systems. Traditionally viewed as metabolic substrates enlisted only in carbohydrate restriction, recent observations underscore the importance of ketone bodies as vital metabolic and signaling mediators when carbohydrates are abundant. Complementing a repertoire of known therapeutic options for diseases of the nervous system, prospective roles for ketone bodies in cancer have arisen, as have intriguing protective roles in heart and liver, opening therapeutic options in obesity-related and cardiovascular disease. Controversies in ketone metabolism and signaling are discussed to reconcile classical dogma with contemporary observations.

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“…CoA transferase is also abundantly expressed in adipose tissue, in which the enzyme that catalyzes the reaction downstream from CoA transferase, AACS (Fig. 3), is dynamically regulated by PPAR␥, a key mediator of adipogenesis and adipocyte function (2,81,233). Adipocyte-specific FAS deficiency increases baseline energy expenditure and improves diet-induced obesity in mice (123).…”

Section: Metabolism Of Ketone Bodies In Health and Diseasementioning

confidence: 99%

Ketone body metabolism and cardiovascular disease

Cotter

Schugar

Crawford

2013

American Journal of Physiology-Heart and Circulatory Physiology

374

304

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Ketone bodies are metabolized through evolutionarily conserved pathways that support bioenergetic homeostasis, particularly in brain, heart, and skeletal muscle when carbohydrates are in short supply. The metabolism of ketone bodies interfaces with the tricarboxylic acid cycle, β-oxidation of fatty acids, de novo lipogenesis, sterol biosynthesis, glucose metabolism, the mitochondrial electron transport chain, hormonal signaling, intracellular signal transduction pathways, and the microbiome. Here we review the mechanisms through which ketone bodies are metabolized and how their signals are transmitted. We focus on the roles this metabolic pathway may play in cardiovascular disease states, the bioenergetic benefits of myocardial ketone body oxidation, and prospective interactions among ketone body metabolism, obesity, metabolic syndrome, and atherosclerosis. Ketone body metabolism is noninvasively quantifiable in humans and is responsive to nutritional interventions. Therefore, further investigation of this pathway in disease models and in humans may ultimately yield tailored diagnostic strategies and therapies for specific pathological states.

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Acetoacetyl-CoA synthetase, a ketone body-utilizing enzyme, is controlled by SREBP-2 and affects serum cholesterol levels

Cited by 47 publications

References 22 publications

An Ester of β‐Hydroxybutyrate Regulates Cholesterol Biosynthesis in Rats and a Cholesterol Biomarker in Humans

An Ester of β‐Hydroxybutyrate Regulates Cholesterol Biosynthesis in Rats and a Cholesterol Biomarker in Humans

Multi-dimensional Roles of Ketone Bodies in Fuel Metabolism, Signaling, and Therapeutics

Ketone body metabolism and cardiovascular disease

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