Pathways and control of ketone body metabolism: on the fringe of lipid biochemistry

doi:10.1016/j.plefa.2003.11.001

Prostaglandins, Leukotrienes and Essential Fatty Acids

Volume 70, Issue 3, March 2004, Pages 243-251

https://doi.org/10.1016/j.plefa.2003.11.001 Get rights and content

Abstract

Ketone bodies become major body fuels during fasting and consumption of a high-fat, low-carbohydrate (ketogenic) diet. Hyperketonemia is associated with potential health benefits. Ketone body synthesis (ketogenesis) is the last recognizable step of lipid energy metabolism, a pathway that links dietary lipids and adipose triglycerides to the Krebs cycle and respiratory chain and has three highly regulated control points: (1) adipocyte lipolysis, (2) mitochondrial fatty acids entry, controlled by the inhibition of carnitine palmityl transferase I by malonyl coenzyme A (CoA) and (3) mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase, which catalyzes the irreversible first step of ketone body synthesis. Each step is suppressed by an elevated circulating insulin level or insulin/glucagon ratio. The utilization of ketone bodies (ketolysis) also determines circulating ketone body levels. Consideration of ketone body metabolism reveals the mechanisms underlying the extreme fragility of dietary ketosis to carbohydrate intake and highlights areas for further study.

Introduction

Ketone body metabolism is highly regulated. Under some conditions, ketosis can develop and ketone bodies become a major body fuel. Ketosis is associated with protection from epilepsy, with weight reduction and with other physiological situations of medical interest, as discussed elsewhere in this issue. The circulating levels of ketone bodies are determined by their rates of production (ketogenesis) and utilization (ketolysis). In this article, we briefly review the pathways of ketogenesis and ketolysis, then examine the characteristics and control of important steps in each pathway.

Section snippets

Ketone body production, flux and utilization: general considerations

Three compounds are grouped together as “ketone bodies”: acetoacetate (AcAc), 3-hydroxybutyrate (3HB) and acetone (Fig. 1). Plasma concentrations of circulating ketone bodies range from <0.1 mM in the postprandial state to up to 6 mM during prolonged fasting [1] and 25 mM in uncontrolled diabetes [2], with considerable interindividual variation. Fasting ketosis develops over hours in children [3] and within days in adults [4], increasing gradually after postprandial nutrients and then tissue

Critical steps of ketone body metabolism

In this review, we focus on the main control points of ketogenesis and the enzymes that are directly involved in the formation and degradation of ketone bodies. The steps with the greatest regulatory power under normal physiological conditions are those determining fatty acid supply to the liver (adipocyte lipolysis), entry of fatty acids into liver mitochondria and derivation of carbon skeletons in mitochondria to ketone body synthesis. We will also discuss the process of ketolysis, which also

Adipocyte lipolysis

Under normal physiological conditions of active ketogenesis, adipose tissue-derived FAs are the principal source of circulating non-esterified fatty acids. Lipolysis is activated by β-adrenergic catecholamines, and is extremely sensitive to suppression by insulin [6] (Fig. 3). Lipolysis is active during fasting, when plasma insulin concentrations are low, and is suppressed postprandially when plasma insulin concentrations are high. While FA release from adipose tissue is clearly important

Mitochondrial entry of fatty acids

The transport of long-chain fatty acids from the cytosol to the mitochondrial matrix occurs in three sequential steps. The system is controlled at the first component, carnitine palmityl transferase I (CPT I), a protein of the outer mitochondrial membrane (Fig. 4) that catalyzes the transfer of a fatty acyl group from cytosolic acyl CoA to carnitine. The acylcarnitine is then transferred to the mitochondrial matrix by carnitine/acylcarnitine translocase. A distinct gene product, CPT II, loosely

Ketogenesis

Ketogenesis is mediated by two enzymes, mitochondrial HMG-CoA synthase (mHS) and HMG-CoA Lyase (HL).

Ketolysis

The ketolytic pathway occurs in extrahepatic tissues, via two reversible reactions that mediate the activation of free AcAc to AcAcCoA and the creation of AcCoA for energy production by terminal oxidative metabolism.

Conclusions

Consideration of the structure and properties of the ketogenic and ketolytic pathways reveals the mechanisms underlying the exquisite sensitivity of lipid energy metabolism and circulating ketone body levels to insulin, and the resulting fragility of diet-induced ketosis following dietary carbohydrate intake. It shows the rationale for the use of the ketogenic diet in some inborn errors of carbohydrate metabolism reviewed elsewhere in this issue, like pyruvate dehydrogenase deficiency and

Acknowledgements

We thank Shupei Wang for long-term collaboration and Jeannette Hernandez for help in preparing this manuscript.

References (78)

C. Des Rosiers et al.
Nonhomogeneous labeling of liver mitochondrial Acetyl-CoA
J. Biol. Chem.
(1991)
A.N. Wick et al.
The effect of concentration on the rate of utilization of beta-hydroxybutyric acid by the rabbit
J. Biol. Chem.
(1941)
Y. Boukaftane et al.
Human mitochondrial HMG CoA synthase (mHS)liver cDNA and partial genomic cloning, chromosome mapping to 1p12-13 and possible role in vertebrate evolution
Genomics
(1994)
F.B. Kraemer et al.
Hormone-sensitive lipasecontrol of intracellular tri-(di-)acylglycerol and cholesteryl ester hydrolysis
J. Lipid. Res.
(2002)
M.W. Anthonsen et al.
Identification of novel phosphorylation sites in hormone-sensitive lipase that are phosphorylated in response to isoproterenol and govern activation properties in vitro
J. Biol. Chem.
(1998)
A.S. Greenberg et al.
Stimulation of lipolysis and hormone-sensitive lipase via the extracellular signal-regulated kinase pathway
J. Biol. Chem.
(2001)
E. Degerman et al.
Structure, Localization, and Regulation of cGMP-inhibited phosphodiesterase (PDE3)
J. Biol. Chem.
(1997)
W.J. Shen et al.
Characterization of the functional interaction of adipocyte lipid-binding protein with hormone-sensitive lipase
J. Biol. Chem.
(2001)
G. Haemmerle et al.
Hormone-sensitive lipase deficiency in mice causes diglyceride accumulation in adipose tissue, muscle, and testis
J. Biol. Chem.
(2002)
A.K. Saha et al.
Activation of malonyl-CoA decarboxylase in rat skeletal muscle by contraction and the AMP-activated protein kinase activator 5-aminoimidazole-4-carboxamide-1-beta -D-ribofuranoside
J. Biol. Chem.
(2000)

N. Kudo et al.

High rates of fatty acid oxidation during reperfusion of ischemic hearts are associated with a decrease in malonyl-CoA levels due to an increase in 5′-AMP-activated protein kinase inhibition of acetyl-CoA carboxylase

J. Biol. Chem.

(1995)

L.A. Witters et al.

Insulin activation of acetyl-CoA carboxylase accompanied by inhibition of the 5′-AMP-activated protein kinase

J. Biol. Chem.

(1992)

G. Arias et al.

The effect of fasting/refeeding and insulin treatment on the expression of the regulatory genes of ketogenesis in intestine and liver of suckling rats

Arch. Biochem. Biophys.

(1997)

D. Serra et al.

Regulation of mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase protein by starvation, fat feeding, and diabetes

Arch. Biochem. Biophys.

(1993)

H.M. Miziorko et al.

3-Hydroxy-3-methylglutaryl-CoA synthase. Participation of acetyl-S-enzyme and enzyme-S-hydroxymethylglutaryl-SCoA intermediates in the reaction

J. Biol. Chem.

(1977)

C. Hipolito-Reis et al.

Factors involved in the control of the activity of enzymes of hepatic ketogenesis during development of the rat

Int. J. Biochem.

(1974)

L.I. Ashmarina et al.

3-Hydroxy-3-methylglutaryl-CoA lyase is present in mouse and human liver peroxisomes

J. Biol. Chem.

(1994)

F. Fraser et al.

Evidence that carnitine palmitoyltransferase I (CPT I) is expressed in microsomes and peroxisomes of rat liver. Distinct immunoreactivity of the N-terminal domain of the microsomal protein

FEBS Lett.

(1999)

A. Fenselau et al.

Ketone body usage by mammals. Acetoacetate substrate inhibition of CoA transferase from various rat tissues

Life. Sci.

(1974)

M.A. Page et al.

Enzymes of ketone-body utilisation in human brain

Lancet

(1971)

G. Fink et al.

Pseudoketogenesis in the perfused rat heart

J. Biol. Chem.

(1988)

M. Karlsson et al.

cDNA cloning, tissue distribution, and identification of the catalytic triad of monoglyceride lipase. Evolutionary relationship to esterases, lysophospholipases, and haloperoxides

J. Biol. Chem.

(1997)

O.E. Owen et al.

Liver and kidney metabolism during prolonged starvation

J. Clin. Invest.

(1969)

D.W. Foster

Diabetes mellitus

J.P. Bonnefont et al.

The fasting test in paediatricsapplication to the diagnosis of pathological hypo- and hyperketotic states

Eur. J. Pediatr.

(1990)

G. Cahill et al.

Hormone-fuel interrelationships during fasting

J. Clin. Invest.

(1966)

M.M. Page et al.

Treatment of diabetic coma with continuous low-dose infusion of insulin

Br. Med. J.

(1974)

R. DeFronzo et al.

Regulation of intermediary metabolism during fasting and feeding

K.S. Polonsky et al.

Secretion and metabolism of insulin, proinsulin and C peptide

J.P. Flatt

On the maximal possible rate of ketogenesis

Diabetes

(1972)

A.J. Garber et al.

Hepatic ketogenesis and gluconeogenesis in humans

J. Clin. Invest.

(1974)

G.A. Reichard et al.

Ketone-body production and oxidation in fasting obese humans

J. Clin. Invest.

(1974)

G.A. Mitchell et al.

Inborn errors of ketone body metabolism

D.H. Williamson et al.

Activities of enzymes involved in acetoacetate utilization in adult mammalian tissues

Biochem. J.

(1971)

E.O. Balasse et al.

Ketone body production and disposaleffects of fasting, diabetes, and exercise

Diabetes Metab. Rev.

(1989)

R.A. Hawkins et al.

Ketone-body utilization by adult and suckling rat brain in vivo

Biochem. J.

(1971)

D.H. Williamson

Ketone body production and metabolism in the fetus and newborn

W.M. Pardridge

Blood-brain barrier transport of glucose, free fatty acids, and ketone bodies

O.E. Owen et al.

Brain metabolism during fasting

J. Clin. Invest.

(1967)

Cited by (291)

Label-free analysis of the β-hydroxybutyricacid drug on mitochondrial redox states repairment in type 2 diabetic mice by resonance raman scattering
2024, Biomedicine and Pharmacotherapy
Mitochondrial redox imbalance underlies the pathophysiology of type2 diabetes mellitus (T2DM), and is closely related to tissue damage and dysfunction. Studies have shown the beneficial effects of dietary strategies that elevate β-hydroxybutyrate (BHB) levels in alleviating T2DM. Nevertheless, the role of BHB has not been clearly elucidated.
We performed a spectral study to visualize the preventive effects of BHB on blood and multiorgan mitochondrial redox imbalance in T2DM mice via using label-free resonance Raman spectroscopy (RRS), and further explored the impact of BHB therapy on the pathology of T2DM mice by histological and biochemical analyses.
Our data revealed that RRS-based mitochondrial redox states assay enabled clear and reliable identification of the improvement of mitochondrial redox imbalance by BHB, evidenced by the reduction of Raman peak intensity at 750 cm⁻¹, 1128 cm⁻¹ and 1585 cm⁻¹ in blood, tissue as well as purified mitochondria of db/db mice and the increase of tissue mitochondrial succinic dehydrogenase (SDH) staining after BHB treatment. Exogenous supplementation of BHB was also found to attenuate T2DM pathology related to mitochondrial redox states, involving organ injury, blood glucose control, insulin resistance and systemic inflammation.
Our findings provide strong evidence for BHB as a potential therapeutic strategy targeting mitochondria for T2DM.
Identifying Acss1, Mtfp1 and Oxct1 as key regulators and promising biomarkers of sarcopenia in various models
2024, Gene
Mitochondrial dysfunction plays a critical role in muscular homeostasis, but the molecular mechanism underlying mitochondrial dynamics and sarcopenia awaits to be uncovered. We all know that malnutrition, cachexia, and type 2 diabetes are significant contributors to the development of sarcopenia.Therefore, we analyzed a bioinformatic analysis on cathectic differentially expressed genes (cDEGs), fasted differentially genes (fDEGs) and mitochondria-related genes. The overlapping genes identified were then validated by RT-qPCR and Western blotting experiments in various sarcopenia mice models and used to predict aging-related muscle loss in humans. First, the correlation analysis and PPI network indicated 6 overlapping candidates (Bdh1, Gdap1, Acss1, Mtfp1, Idh2, Oxct1) may constitute a regulatory effect in mitochondrial dynamics and muscle wasting. Next, we successfully established fasted, Lewis lung carcinoma (LLC) and Diabetes Mellitus (DM) induced sarcopenia mice models and verified that Acss1, Mtfp1 and Oxct1 shared common and significant variation tendency in these sarcopenia mice models. Further-more, Pearson correlation analysis showed that Acss1 was negatively related to the weight of gastrocnemius while Mtfp1 and Oxct1 displayed a significantly positive correlation with gastrocnemius weight in sarcopenic mice model induced by LLC, fasting and DM. What’s more, ROC analysis based on human aging-related datasets indicated Acss1, Mtfp1, Oxct1 had outstanding diagnostic capabilities for sarcopenia. In general, we identified three hub genes (Acss1, Mtfp1 and Oxct1) that are strongly associated with mitochondrial dysfunction in sarcopenia and may provide novel and reliable indicators for screening, diagnosis, and prognosis, as well as potential therapeutic targets for patients with sarcopenia.
A novel therapeutic target for kidney diseases: Lessons learned from starvation response
2024, Pharmacology and Therapeutics
The prevalence of chronic kidney disease (CKD) is increasing worldwide, making the disease an urgent clinical challenge. Caloric restriction has various anti-aging and organ-protective effects, and unraveling its molecular mechanisms may provide insight into the pathophysiology of CKD. In response to changes in nutritional status, intracellular nutrient signaling pathways show adaptive changes. When nutrients are abundant, signals such as mechanistic target of rapamycin complex 1 (mTORC1) are activated, driving cell proliferation and other processes. Conversely, others, such as sirtuins and AMP-activated protein kinase, are activated during energy scarcity, in an attempt to compensate. Autophagy, a cellular self-maintenance mechanism that is regulated by such signals, has also been reported to contribute to the progression of various kidney diseases. Furthermore, in recent years, ketone bodies, which have long been considered to be detrimental, have been reported to play a role as starvation signals, and thereby to have renoprotective effects, via the inhibition of mTORC1. Therefore, in this review, we discuss the role of mTORC1, which is one of the most extensively studied nutrient-related signals associated with kidney diseases, autophagy, and ketone body metabolism; and kidney energy metabolism as a novel therapeutic target for CKD.
Kinin B1 receptor controls maternal adiponectin levels and influences offspring weight gain
2023, iScience
Given the importance of the kinin B1 receptor in insulin and leptin hormonal regulation, which in turn is crucial in maternal adaptations to ensure nutrient supply to the fetus, we investigated the role of this receptor in maternal metabolism and fetoplacental development. Wild-type and kinin B1 receptor-deficient (B1KO) female mice were mated with male mice of the opposite genotype. Consequently, the entire litter was heterozygous for kinin B1 receptor, ensuring that there would be no influence of offspring genotype on the maternal phenotype. Maternal kinin B1 receptor blockade reduces adiponectin secretion by adipose tissue ex vivo, consistent with lower adiponectin levels in pregnant B1KO mice. Furthermore, fasting insulinemia also increased, which was associated with placental insulin resistance, reduced placental glycogen accumulation, and heavier offspring. Therefore, we propose the combination of chronic hyperinsulinemia and reduced adiponectin secretion in B1KO female mice create a maternal obesogenic environment that results in heavier pups.
Dietary pattern and hepatic lipid metabolism
2023, Liver Research
The liver is the leading site for lipid metabolism, involving not only fatty acid beta-oxidation but also de novo synthesis of endogenous triglycerides and ketogenesis. The liver maintains systemic lipid homeostasis by regulating lipid synthesis, catabolism, and transportation. Dysregulation of hepatic lipid metabolism precipitates disorders, such as non-alcoholic fatty liver disease (NAFLD), affecting the whole body. Thus, comprehending and studying hepatic lipid metabolism is crucial for preventing and treating metabolic liver diseases. Traditionally, researchers have investigated the impact of a single nutrient on hepatic lipid metabolism. However, real-life dietary patterns encompass diverse nutrients rather than single components. In recent years, there have been increased studies and notable progress regarding the effects of distinct dietary patterns on hepatic lipid metabolism. This review summarizes the influence of diverse dietary patterns on hepatic lipid metabolism, elucidating underlying molecular mechanisms and appraising the therapeutic potential of dietary patterns in managing hepatic steatosis.
Bioaccumulation and metabolic impact of environmental PFAS residue on wild-caught urban wetland tiger snakes (Notechis scutatus)
2023, Science of the Total Environment
PFAS contamination of urban waters is widespread but understanding the biological impact of its accumulation is limited to humans and common ecotoxicological model organisms. Here, we combine PFAS exposure and bioaccumulation patterns with whole organism responses and omics-based ecosurveillance methods to investigate the potential impacts of PFAS on a top predator of wetlands, the tiger snake (Notechis scutatus). Tiger snakes (18 male and 17 female) were collected from four wetlands with varying PFAS chemical profiles and concentrations in Perth, Western Australia. Tiger snake livers were tested for 28 known PFAS compounds, and Σ28PFAS in liver tissues ranged between 322 ± 193 μg/kg at the most contaminated site to 1.31 ± 0.86 μg/kg at the least contaminated site. The dominant PFAS compound detected in liver tissues was PFOS. Lower body condition was associated with higher liver PFAS, and male snakes showed signs of high bioaccumulation whereas females showed signs of maternal offloading. Biochemical profiles of snake muscle, fat (adipose tissue), and gonads were analysed using a combination of liquid chromatography triple quadrupole (QqQ) and quadrupole time-of-flight (QToF) mass spectrometry methodologies. Elevated PFAS was associated with enriched energy production and maintenance pathways in the muscle, and had weak associations with energy-related lipids in the fat tissue, and lipids associated with cellular genesis and spermatogenesis in the gonads. These findings demonstrate the bioavailability of urban wetland PFAS in higher-order reptilian predators and suggest a negative impact on snake health and metabolic processes. This research expands on omics-based ecosurveillance tools for informing mechanistic toxicology and contributes to our understanding of the impact of PFAS residue on wildlife health to improve risk management and regulation.

View all citing articles on Scopus

View full text

Pathways and control of ketone body metabolism: on the fringe of lipid biochemistry

Abstract

Introduction

Section snippets

Ketone body production, flux and utilization: general considerations

Critical steps of ketone body metabolism

Adipocyte lipolysis

Mitochondrial entry of fatty acids

Ketogenesis

Ketolysis

Conclusions

Acknowledgements

J. Biol. Chem.

J. Biol. Chem.

Genomics

J. Lipid. Res.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Arch. Biochem. Biophys.

Arch. Biochem. Biophys.

J. Biol. Chem.

Int. J. Biochem.

J. Biol. Chem.

FEBS Lett.

Life. Sci.

Lancet

J. Biol. Chem.

J. Biol. Chem.

Liver and kidney metabolism during prolonged starvation

J. Clin. Invest.

Diabetes mellitus

The fasting test in paediatricsapplication to the diagnosis of pathological hypo- and hyperketotic states

Eur. J. Pediatr.

Hormone-fuel interrelationships during fasting

J. Clin. Invest.

Treatment of diabetic coma with continuous low-dose infusion of insulin

Br. Med. J.

Regulation of intermediary metabolism during fasting and feeding

Secretion and metabolism of insulin, proinsulin and C peptide

On the maximal possible rate of ketogenesis

Diabetes

Hepatic ketogenesis and gluconeogenesis in humans

J. Clin. Invest.

Ketone-body production and oxidation in fasting obese humans

J. Clin. Invest.

Inborn errors of ketone body metabolism

Activities of enzymes involved in acetoacetate utilization in adult mammalian tissues

Biochem. J.

Ketone body production and disposaleffects of fasting, diabetes, and exercise

Diabetes Metab. Rev.

Ketone-body utilization by adult and suckling rat brain in vivo

Biochem. J.

Ketone body production and metabolism in the fetus and newborn

Blood-brain barrier transport of glucose, free fatty acids, and ketone bodies

Brain metabolism during fasting

J. Clin. Invest.