Ketone bodies as signaling metabolites

Newman, John C.; Verdin, Eric

doi:10.1016/j.tem.2013.09.002

Cited by 776 publications

(719 citation statements)

References 140 publications

(195 reference statements)

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“…The production of ketone bodies, or ketogenesis, mainly occurs in the liver where acetyl-CoA is first converted to AcAc, which is further catalyzed by β-hydroxybutyrate dehydrogenase (BDH1) to produce β-HB. While acetone is unable to be further metabolized to produce ATP, both AcAc and -HB are exported into bloodstream and consumed by extra-hepatic tissues, such as muscle, kidney or brain [11]. Of note, ketone bodies are also able to pass through the blood-brain barrier, entering the brain to serve as a major energy source during starvation [12].…”

Section: Introductionmentioning

confidence: 99%

Hepatocellular carcinoma redirects to ketolysis for progression under nutrition deprivation stress

et al. 2016

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Cancer cells are known for their capacity to rewire metabolic pathways to support survival and proliferation under various stress conditions. Ketone bodies, though produced in the liver, are not consumed in normal adult liver cells. We find here that ketone catabolism or ketolysis is re-activated in hepatocellular carcinoma (HCC) cells under nutrition deprivation conditions. Mechanistically, 3-oxoacid CoA-transferase 1 (OXCT1), a rate-limiting ketolytic enzyme whose expression is suppressed in normal adult liver tissues, is re-induced by serum starvation-triggered mTORC2-AKT-SP1 signaling in HCC cells. Moreover, we observe that enhanced ketolysis in HCC is critical for repression of AMPK activation and protects HCC cells from excessive autophagy, thereby enhancing tumor growth. Importantly, analysis of clinical HCC samples reveals that increased OXCT1 expression predicts higher patient mortality. Taken together, we uncover here a novel metabolic adaptation by which nutrition-deprived HCC cells employ ketone bodies for energy supply and cancer progression.

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Section: Introductionmentioning

confidence: 99%

Hepatocellular carcinoma redirects to ketolysis for progression under nutrition deprivation stress

et al. 2016

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“…15 The synthesis of ketone bodies, such as β-hydroxybutyrate (βHB) and acetoacetate (AcAc), is controlled by the rate-limiting enzyme, mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2). 16 Recently, βHB has also been shown to act as an endogenous inhibitor of HDACs, 17 which are known to regulate intestinal epithelial differentiation. 18 Circulating concentrations of βHB can increase to as much as 6-8 mM during prolonged fasting and caloric restriction 16,17 when the liver switches to fatty acid oxidation, and even to 25 mM in diabetic ketoacidosis.…”

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confidence: 99%

“…16 Recently, βHB has also been shown to act as an endogenous inhibitor of HDACs, 17 which are known to regulate intestinal epithelial differentiation. 18 Circulating concentrations of βHB can increase to as much as 6-8 mM during prolonged fasting and caloric restriction 16,17 when the liver switches to fatty acid oxidation, and even to 25 mM in diabetic ketoacidosis. These nutritional states are associated with altered intestinal integrity, 19 but it is unknown whether ketone bodies have a role in the maintenance of intestinal homeostasis.…”

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confidence: 99%

Ketogenesis contributes to intestinal cell differentiation

et al. 2016

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The intestinal epithelium undergoes a continual process of proliferation, differentiation and apoptosis. Previously, we have shown that the PI3K/Akt/mTOR pathway has a critical role in intestinal homeostasis. However, the downstream targets mediating the effects of mTOR in intestinal cells are not known. Here, we show that the ketone body β-hydroxybutyrate (βHB), an endogenous inhibitor of histone deacetylases (HDACs) induces intestinal cell differentiation as noted by the increased expression of differentiation markers (Mucin2 (MUC2), lysozyme, IAP, sucrase-isomaltase, KRT20, villin, Caudal-related homeobox transcription factor 2 (CDX2) and p21 Waf1 ). Conversely, knockdown of the ketogenic mitochondrial enzyme hydroxymethylglutaryl CoA synthase 2 (HMGCS2) attenuated spontaneous differentiation in the human colon cancer cell line Caco-2. Overexpression of HMGCS2, which we found is localized specifically in the more differentiated portions of the intestinal mucosa, increased the expression of CDX2, thus further suggesting the contributory role of HMGCS2 in intestinal differentiation. In addition, mice fed a ketogenic diet demonstrated increased differentiation of intestinal cells as noted by an increase in the enterocyte, goblet and Paneth cell lineages. Moreover, we showed that either knockdown of mTOR or inhibition of mTORC1 with rapamycin increases the expression of HMGCS2 in intestinal cells in vitro and in vivo, suggesting a possible cross-talk between mTOR and HMGCS2/βHB signaling in intestinal cells. In contrast, treatment of intestinal cells with βHB or feeding mice with a ketogenic diet inhibits mTOR signaling in intestinal cells. Together, we provide evidence showing that HMGCS2/βHB contributes to intestinal cell differentiation. Our results suggest that mTOR acts cooperatively with HMGCS2/βHB to maintain intestinal homeostasis.

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“…KBs in cell culture studies have been demonstrated to act as metabolic inhibitors of glycolytic ATP production and cell growth in several cancer lines [21,22] and also have demonstrable action as signaling molecules with broad cancer inhibiting effects [23][24][25].…”

Section: Rationalementioning

confidence: 99%

An Evolutionary and Mechanistic Perspective on Dietary Carbohydrate Restriction in Cancer Prevention

Fine¹,

Champ²,

Feinman³

et al. 2016

jevohealth

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The confluence of basic cell biochemistry, epidemiological and anthropologic evidence points to high dietary carbohydrate and the associated disruption of the glucose-insulin axis as causes of the current increase in metabolic disorders, metabolic syndrome, hypertension and cardiovascular disease. This hyperinsulinemic state likely contributes, as well, to an increased mutagenic microenvironment, with increased risk for cancer. This critical review discusses these risks in their historical and evolutionary context. The evidence supports the benefits of lowering the glycemic load of the diet as a preventive measure against the development of cancer.

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Ketone bodies as signaling metabolites

Cited by 776 publications

References 140 publications

Hepatocellular carcinoma redirects to ketolysis for progression under nutrition deprivation stress

Hepatocellular carcinoma redirects to ketolysis for progression under nutrition deprivation stress

Ketogenesis contributes to intestinal cell differentiation

An Evolutionary and Mechanistic Perspective on Dietary Carbohydrate Restriction in Cancer Prevention

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