Diminished ketone interconversion, hepatic TCA cycle flux, and glucose production in D-β-hydroxybutyrate dehydrogenase hepatocyte-deficient mice

Stagg, David B.; Gillingham, Jacob R.; Nelson, Alisa B.; Lengfeld, Justin; d’Avignon, D. André; Puchalska, Patrycja; Crawford, Peter A.

doi:10.1016/j.molmet.2021.101269

Cited by 23 publications

(20 citation statements)

References 45 publications

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“…Surprisingly, we observed about 1/3 of normal blood BHB concentrations under KD in the liver KO (Extended Fig. 10d , k) , suggesting a role for non-hepatic ketogenesis under the strong stimulus of KD in compensating for loss of hepatic BHB production 35,39–41 . We confirmed efficacy of the knockout via RT-qPCR showing increased induction of Hmgcs2 with KD, emphasizing ketogenesis, but an insignificant change in Bdh1 , supporting the lack of AcAc to BHB conversion in livers of both male and female liver BDH1 KOs (Extended Fig.…”

Section: Resultsmentioning

confidence: 78%

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Ketone body metabolism declines with age in mice in a sex-dependent manner

Eap

Nomura

Panda

et al. 2022

Preprint

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Understanding how our cells maintain energy homeostasis has long been a focus of aging biology. A decline in energy metabolism is central to many age-related diseases such as Alzheimer's disease, heart failure, frailty, and delirium. Intervening on pathways involved in energy homeostasis can extend healthy lifespan. When the primary energy substrate glucose is scarce, mice and humans can partially switch cellular energetic needs to fat-derived ketone bodies (i.e., beta-hydroxybutyrate (BHB), acetoacetate, acetone). Aging is associated with glucose intolerance and insulin insensitivity, yet, surprisingly, what role ketone body metabolism might play in compensating for impaired glucose utilization in age-related diseases is understudied. Here, we investigate how endogenous ketone body production and utilization pathways are modulated by age across the lifespan of male and female C57BL/6N mice (3 mo old, 12 mo old, 22 mo old). We show how different ages have different metabolic and gene expression responses to 1-week ketogenic diet (KD). We hypothesized that there would be a compensatory ketogenic response with age but instead saw declines in plasma BHB concentrations under fasting and non-fasting conditions with strong sexual dimorphism. Under KD, both sexes increased BHB concentrations at all ages, but only males showed strong gene expression induction. We also observed tissue-specific changes with age in baseline ketone metabolism, and surprising induction of extrahepatic ketogenic genes under KD. We found significant residual blood concentrations of BHB in KD even after a knockout of liver BHB production. Overall, these findings show that older mice have impaired non-fasting ketogenesis but are capable of increasing their ketogenic capacity under stimulation (i.e., KD) to meet energetic demands in aging. Therapies to augment non-fasting ketogenesis or provide exogenous ketones may be useful to improve energy homeostasis in diseases and conditions of aging.

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Section: Resultsmentioning

confidence: 78%

“…Finally, to directly test if induced extra-hepatic ketogenesis meaningfully contributes to blood BHB concentrations under KD, we generated a liver-specific knockout (KO) mouse of Bdh1 (Albumin-Cre; Bdh1 fl/fl ) that should produce only AcAc, not BHB, from the liver 35 (Extended Fig. 10a) .…”

Section: Resultsmentioning

confidence: 99%

Ketone body metabolism declines with age in mice in a sex-dependent manner

Eap

Nomura

Panda

et al. 2022

Preprint

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“…IF also confers a protective effect against oxidative stress and inflammation by activating antistress responses, including nuclear respiratory factor (Nrf )-1, Nrf-2 and mammalian target of rapamycin (mTOR) pathways [16,17]. Moreover, IF increases NAD + /NADH through altering cellular metabolic processes which leads to the Sirtuin proteins activation [18]. We have recently shown that, Sirt3, which is a member of the Sirtuin family and is primarily located in mitochondria in the cells, plays an essential role in regulating cellular apoptosis and autophagy after oxidative neuronal stress [19].…”

Section: Introductionmentioning

confidence: 99%

Intermittent fasting reduces neuroinflammation in intracerebral hemorrhage through the Sirt3/Nrf2/HO-1 pathway

Dai

Wei

Zhang

et al. 2022

J Neuroinflammation

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Background Inflammation contributes to the poor prognosis of intracerebral hemorrhage (ICH). Intermittent fasting (IF) has been shown to be protective against inflammation in multiple pathogenic processes. In the present study, we aimed to investigated the beneficial effects of IF in attenuating neuroinflammation and neurological deficits in a mouse model of ICH and to investigate the underlying mechanism. Methods ICH was modeled by intrastriatal injection of autologous blood and IF was modeled by every-other-day feeding in male control mice (C57BL/6), mice with and microglia specific knockout Sirt3f/f;Cx3cr1-Cre (Sirt3 cKO), and Sirt3f/f (wild-type) mice. Brain tissues and arterial blood were harvested at 1, 3, 7 and 28 days after ICH for immunohistochemistry analysis of Iba-1, DARPP-32 and HO-1, morphological analysis by HE staining and inflammatory factor release tests by ELISA. Neurological functions were approached by corner test and cylinder test. Fluorescent double-labeled staining of Iba-1 with CD16, Arg1 or Sirt3 was used to provide direct image of co-expression of these molecules in microglia. TUNEL, cleaved caspase-3 and Nissl staining was performed to evaluate cellular injuries. Results IF alleviated neurological deficits in both acute and chronic phases after ICH. Morphologically, IF enhanced hematoma clearance, reduced brain edema in acute phase and attenuated striatum atrophy in chronic phase. In addition, IF decreased the numbers of TUNEL+ cells and increased Nissl+ neuron number at day 1, 3 and 7 after ICH. IF suppressed CD16+Iba-1+ microglia activation at day 3 after ICH and reduced inflammatory releases, such as IL-1β and TNF-α. The above effects of IF were attenuated by microglia Sirt3 deletion partly because of an inhibition of Nrf2/HO-1 signaling pathway. Interestingly, IF increased Iba-1+ microglia number at day 7 which mainly expressed Arg1 while decreased the proinflammatory factor levels. In mice with microglia-specific Sirt3 deletion, the effects of IF on Iba-1+ microglia activation and anti-inflammatory factor expressions were attenuated when compared with wild-type Sirt3f/f mice. Conclusions IF protects against ICH by suppressing the inflammatory responses via the Sirt3/Nrf2/HO-1 pathway.

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“…To quantify energy metabolites using methods described in 46,47 enabled with the optional "-q" option; 3bp sliding-window trimming from 3' end requiring minimum Q30. Quality control was completed by FastQC.…”

Section: Isotope Tracing Untargeted Metabolomicsmentioning

confidence: 99%

Mitochondrial citrate metabolism and efflux regulates trophoblast differentiation

Mahr

Jena

Nashif

et al. 2023

Preprint

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Cytotrophoblasts fuse to form and renew syncytiotrophoblasts necessary to maintain placental health throughout gestation. During cytotrophoblast to syncytiotrophoblast differentiation, cells undergo regulated metabolic and transcriptional reprogramming. Mitochondria play a critical role in differentiation events in cellular systems, thus we hypothesized that mitochondrial metabolism played a central role in trophoblast differentiation. In this work, we employed static and stable isotope tracing untargeted metabolomics methods along with gene expression and histone acetylation studies in an established cell culture model of trophoblast differentiation. Trophoblast differentiation was associated with increased abundance of the TCA cycle intermediates citrate and α-ketoglutarate. Citrate was preferentially exported from mitochondria in the undifferentiated state but was retained to a larger extent within mitochondria upon differentiation. Correspondingly, differentiation was associated with decreased expression of the mitochondrial citrate transporter (CIC). CRISPR/Cas9 disruption of the mitochondrial citrate carrier showed that CIC is required for biochemical differentiation of trophoblasts. Loss of CIC resulted in broad alterations in gene expression and histone acetylation. These gene expression changes were partially rescued through acetate supplementation. Taken together, these results highlight a central role for mitochondrial citrate metabolism in orchestrating histone acetylation and gene expression during trophoblast differentiation.

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Diminished ketone interconversion, hepatic TCA cycle flux, and glucose production in D-β-hydroxybutyrate dehydrogenase hepatocyte-deficient mice

Cited by 23 publications

References 45 publications

Ketone body metabolism declines with age in mice in a sex-dependent manner

Ketone body metabolism declines with age in mice in a sex-dependent manner

Intermittent fasting reduces neuroinflammation in intracerebral hemorrhage through the Sirt3/Nrf2/HO-1 pathway

Mitochondrial citrate metabolism and efflux regulates trophoblast differentiation

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