The Hepatic Monocarboxylate Transporter 1 (MCT1) Contributes to the Regulation of Food Anticipation in Mice

Daily recurring events can be predicted by animals based on their internal circadian timing system. However, independently from the suprachiasmatic nuclei (SCN), the central pacemaker of the circadian system in mammals, restriction of food access to a particular time of day elicits food anticipatory activity (FAA). This suggests an involvement of other central and/or peripheral clocks as well as metabolic signals in this behavior. One of the metabolic signals that is important for FAA under combined caloric and temporal food restriction is β-hydroxybutyrate (βOHB). Here we show that the monocarboxylate transporter 1 (Mct1), which transports ketone bodies such as βOHB across membranes of various cell types, is involved in FAA. In particular, we show that lack of the Mct1 gene in the liver, but not in neuronal or glial cells, reduces FAA in mice. This is associated with a reduction of βOHB levels in the blood. Our observations suggest an important role of ketone bodies and its transporter Mct1 in FAA under caloric and temporal food restriction.

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Transport of ketone bodies and lactate in the sheep ruminal epithelium by monocarboxylate transporter 1

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00268.2001 ◽

2002 ◽

Vol 283 (5) ◽

pp. G1139-G1146 ◽

Cited By ~ 55

Author(s):

Frank Müller ◽

Korinna Huber ◽

Helga Pfannkuche ◽

Jörg R. Aschenbach ◽

Gerhard Breves ◽

...

Keyword(s):

Epithelial Cells ◽

Cultured Cells ◽

Ketone Bodies ◽

Short Chain Fatty Acids ◽

Monocarboxylate Transporter ◽

Monocarboxylate Transporter 1 ◽

Protein Levels ◽

Ruminal Epithelium ◽

Intracellular Metabolism ◽

Acid Extrusion

Due to intensive intracellular metabolism of short-chain fatty acids, ruminal epithelial cells generate large amounts of d-β-hydroxybutyric acid, acetoacetic acid, and lactic acid. These acids have to be extruded from the cytosol to avoid disturbances of intracellular pH (pHi). To evaluate acid extrusion, pHi was studied in cultured ruminal epithelial cells of sheep using the pH-sensitive fluorescent dye 2′,7′-bis(2-carboxyethyl)-5(6)-carboxyfluorescein. Extracellular addition of d-β-hydroxybutyrate, acetoacetate, or lactate (20 mM) resulted in intracellular acidification. Vice versa, removing extracellulard-β-hydroxybutyrate, acetoacetate, or lactate after preincubation with the respective monocarboxylate induced an increase of pHi. Initial rate of pHi decrease as well as of pHi recovery was strongly inhibited by pCMBS (400 μM) and phloretin (20 μM). Both cultured cells and intact ruminal epithelium were tested for the possible presence of proton-linked monocarboxylate transporter (MCT) on both the mRNA and protein levels. With the use of RT-PCR, mRNA encoding for MCT1 isoform was demonstrated in cultured ruminal epithelial cells and the ruminal epithelium. Immunostaining with MCT1 antibodies intensively labeled cultured ruminal epithelial cells and cells located in the stratum basale of the ruminal epithelium. In conclusion, our data indicate that MCT1 is expressed in the stratum basale of the ruminal epithelium and may function as a main mechanism for removing ketone bodies and lactate together with H+ from the cytosol into the blood.

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Substrate and inhibitor specificities of the monocarboxylate transporters of single rat heart cells

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1996.270.2.h476 ◽

1996 ◽

Vol 270 (2) ◽

pp. H476-H484 ◽

Cited By ~ 16

Author(s):

X. Wang ◽

A. J. Levi ◽

A. P. Halestrap

Keyword(s):

Rat Heart ◽

Ketone Bodies ◽

Cell Types ◽

Isolated Rat Heart ◽

Monocarboxylate Transporter ◽

Disulfonic Acid ◽

Heart Cells ◽

Maximum Reaction Rate ◽

High Concentrations ◽

Rat Heart Cells

We have used the intracellular pH-sensitive fluorescent dye 2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein (BCECF) to characterize the substrate and inhibitor specificity of monocarboxylate transport into isolated rat heart cells. Further evidence was obtained for the presence of two lactate carriers present in heart cells (Wang et al., Biochem. J. 290: 249-258, 1993) both distinct from the recently cloned monocarboxylate transporter isoform 1 (MCT-1) found in many other cell types. Only one isoform was potently inhibited by alpha-cyano-4-hydroxycinnamate [CHC; inhibitor constant (Ki) 190 microM] and the stilbene disulfonates 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (Ki 79 microM) and 4,4'-dinitrostilbene-2,2'-disulfonate (Ki of cis- and trans-isomers 38 and 171 microM, respectively; neither isomer inhibits MCT-1). The second carrier had a Ki of approximately 3 mM for CHC and 0.5-2 mM for the stilbene disulfonates. Thus, unlike in many other tissues, in rat heart cells these inhibitors are not effective at blocking lactate transport totally unless used at very high concentrations. Both carriers were inhibited by 3-isobutyl-1-methylxanthine (Ki 340 microM) and neither by 5-nitro-2-(3-phenylpropylamino)benzoate (a potent inhibitor of MCT-1). The overall Michaelis constant (Km) and maximum reaction rate (Vmax) for transport of a variety of substituted monocarboxylates (C2-C5) were determined, although it was not possible to elucidate the kinetic parameters of the two isoforms. Of physiological interest, the ketone bodies D-beta-hydroxybutyrate and acetoacetate had K(m) values of 10 and 5.4 mM, respectively. Vmax values were similar to those of L-lactate and pyruvate and indicate that transport could limit rates of utilization of ketone bodies. No stereoselectivity for L-over D-isomers of 2-chloro or 2-hydroxy acids was observed.

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Mechanisms of Communication in the Mammalian Circadian Timing System

International Journal of Molecular Sciences ◽

10.3390/ijms20020343 ◽

2019 ◽

Vol 20 (2) ◽

pp. 343 ◽

Cited By ~ 23

Author(s):

Mariana Astiz ◽

Isabel Heyde ◽

Henrik Oster

Keyword(s):

Current Knowledge ◽

The Body ◽

Dark Cycle ◽

Timing System ◽

Circadian Timing System ◽

Neuroendocrine Mechanisms ◽

Peripheral Clocks ◽

Central Pacemaker ◽

And Function ◽

Therapeutic Settings

24-hour rhythms in physiology and behaviour are organized by a body-wide network of endogenous circadian clocks. In mammals, a central pacemaker in the hypothalamic suprachiasmatic nucleus (SCN) integrates external light information to adapt cellular clocks in all tissues and organs to the external light-dark cycle. Together, central and peripheral clocks co-regulate physiological rhythms and functions. In this review, we outline the current knowledge about the routes of communication between the environment, the main pacemakers and the downstream clocks in the body, focusing on what we currently know and what we still need to understand about the communication mechanisms by which centrally and peripherally controlled timing signals coordinate physiological functions and behaviour. We highlight recent findings that shed new light on the internal organization and function of the SCN and neuroendocrine mechanisms mediating clock-to-clock coupling. These findings have implications for our understanding of circadian network entrainment and for potential manipulations of the circadian clock system in therapeutic settings.

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Differential Response of Hippocampal and Cerebrocortical Autophagy and Ketone Body Metabolism to the Ketogenic Diet

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.733607 ◽

2021 ◽

Vol 15 ◽

Author(s):

Daniela Liśkiewicz ◽

Arkadiusz Liśkiewicz ◽

Marta M. Nowacka-Chmielewska ◽

Mateusz Grabowski ◽

Natalia Pondel ◽

...

Keyword(s):

Frontal Cortex ◽

Ketogenic Diet ◽

Ketone Body ◽

Brain Aging ◽

Ketone Bodies ◽

Monocarboxylate Transporter ◽

Proper Function ◽

Monocarboxylate Transporter 1 ◽

Coa Transferase ◽

Ketone Body Metabolism

Experimental and clinical data support the neuroprotective properties of the ketogenic diet and ketone bodies, but there is still a lot to discover to comprehensively understand the underlying mechanisms. Autophagy is a key mechanism for maintaining cell homeostasis, and therefore its proper function is necessary for preventing accelerated brain aging and neurodegeneration. Due to many potential interconnections, it is possible that the stimulation of autophagy may be one of the mediators of the neuroprotection afforded by the ketogenic diet. Recent studies point to possible interconnections between ketone body metabolism and autophagy. It has been shown that autophagy is essential for hepatic and renal ketogenesis in starvation. On the other hand, exogenous ketone bodies modulate autophagy both in vitro and in vivo. Many regional differences occur between brain structures which concern i.e., metabolic responses and autophagy dynamics. The aim of the present study was to evaluate the influence of the ketogenic diet on autophagic markers and the ketone body utilizing and transporting proteins in the hippocampus and frontal cortex. C57BL/6N male mice were fed with two ketogenic chows composed of fat of either animal or plant origins for 4 weeks. Markers of autophagosome formation as well as proteins associated with ketolysis (BDH1—3-hydroxybutyrate dehydrogenase 1, SCOT/OXCT1—succinyl CoA:3-oxoacid CoA transferase), ketone transport (MCT1—monocarboxylate transporter 1) and ketogenesis (HMGCL, HMGCS2) were measured. The hippocampus showed a robust response to nutritional ketosis in both changes in the markers of autophagy as well as the levels of ketone body utilizing and transporting proteins, which was also accompanied by increased concentrations of ketone bodies in this brain structure, while subtle changes were observed in the frontal cortex. The magnitude of the effects was dependent on the type of ketogenic diet used, suggesting that plant fats may exert a more profound effect on the orchestrated upregulation of autophagy and ketone body metabolism markers. The study provides a foundation for a deeper understanding of the possible interconnections between autophagy and the neuroprotective efficacy of nutritional ketosis.

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Supplemental Material for Binge Eating For Sucrose Is Time of Day Dependent and Independent of Food Restriction: Effects on Mesolimbic Structures

Behavioral Neuroscience ◽

10.1037/bne0000364.supp ◽

2020 ◽

Keyword(s):

Binge Eating ◽

Food Restriction ◽

Time Of Day

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Faculty Opinions recommendation of A novel nutrient sensing mechanism underlies substrate-induced regulation of monocarboxylate transporter-1.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717991560.793473364 ◽

2013 ◽

Author(s):

Bruno Stieger

Keyword(s):

Nutrient Sensing ◽

Monocarboxylate Transporter ◽

Monocarboxylate Transporter 1 ◽

Sensing Mechanism

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Treatment of Lymphoid and Myeloid Malignancies by Immunomodulatory Drugs

Cardiovascular & Haematological Disorders - Drug Targets ◽

10.2174/1871529x18666180522073855 ◽

2019 ◽

Vol 19 (1) ◽

pp. 51-78 ◽

Cited By ~ 3

Author(s):

Ota Fuchs

Keyword(s):

Clinical Trials ◽

Transcription Factors ◽

Ubiquitin Ligase ◽

Mononuclear Cells ◽

E3 Ubiquitin Ligase ◽

Lymphocytic Leukemia ◽

Monocarboxylate Transporter ◽

Immunomodulatory Drugs ◽

Monocarboxylate Transporter 1 ◽

Argonaute 2

Thalidomide and its derivatives (lenalidomide, pomalidomide, avadomide, iberdomide hydrochoride, CC-885 and CC-90009) form the family of immunomodulatory drugs (IMiDs). Lenalidomide (CC5013, Revlimid®) was approved by the US FDA and the EMA for the treatment of multiple myeloma (MM) patients, low or intermediate-1 risk transfusion-dependent myelodysplastic syndrome (MDS) with chromosome 5q deletion [del(5q)] and relapsed and/or refractory mantle cell lymphoma following bortezomib. Lenalidomide has also been studied in clinical trials and has shown promising activity in chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL). Lenalidomide has anti-inflammatory effects and inhibits angiogenesis. Pomalidomide (CC4047, Imnovid® [EU], Pomalyst® [USA]) was approved for advanced MM insensitive to bortezomib and lenalidomide. Other IMiDs are in phases 1 and 2 of clinical trials. Cereblon (CRBN) seems to have an important role in IMiDs action in both lymphoid and myeloid hematological malignancies. Cereblon acts as the substrate receptor of a cullin-4 really interesting new gene (RING) E3 ubiquitin ligase CRL4CRBN. This E3 ubiquitin ligase in the absence of lenalidomide ubiquitinates CRBN itself and the other components of CRL4CRBN complex. Presence of lenalidomide changes specificity of CRL4CRBN which ubiquitinates two transcription factors, IKZF1 (Ikaros) and IKZF3 (Aiolos), and casein kinase 1α (CK1α) and marks them for degradation in proteasomes. Both these transcription factors (IKZF1 and IKZF3) stimulate proliferation of MM cells and inhibit T cells. Low CRBN level was connected with insensitivity of MM cells to lenalidomide. Lenalidomide decreases expression of protein argonaute-2, which binds to cereblon. Argonaute-2 seems to be an important drug target against IMiDs resistance in MM cells. Lenalidomide decreases also basigin and monocarboxylate transporter 1 in MM cells. MM cells with low expression of Ikaros, Aiolos and basigin are more sensitive to lenalidomide treatment. The CK1α gene (CSNK1A1) is located on 5q32 in commonly deleted region (CDR) in del(5q) MDS. Inhibition of CK1α sensitizes del(5q) MDS cells to lenalidomide. CK1α mediates also survival of malignant plasma cells in MM. Though, inhibition of CK1α is a potential novel therapy not only in del(5q) MDS but also in MM. High level of full length CRBN mRNA in mononuclear cells of bone marrow and of peripheral blood seems to be necessary for successful therapy of del(5q) MDS with lenalidomide. While transfusion independence (TI) after lenalidomide treatment is more than 60% in MDS patients with del(5q), only 25% TI and substantially shorter duration of response with occurrence of neutropenia and thrombocytopenia were achieved in lower risk MDS patients with normal karyotype treated with lenalidomide. Shortage of the biomarkers for lenalidomide response in these MDS patients is the main problem up to now.

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Monocarboxylate transporter-1 (MCT1) protein expression in head and neck cancer affects clinical outcome

Scientific Reports ◽

10.1038/s41598-021-84019-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Martin Leu ◽

J. Kitz ◽

Y. Pilavakis ◽

S. Hakroush ◽

H. A. Wolff ◽

...

Keyword(s):

Cell Membrane ◽

Protein Expression ◽

Head And Neck ◽

Cox Regression ◽

Locally Advanced ◽

Monocarboxylate Transporter ◽

Positive Staining ◽

Monocarboxylate Transporter 1 ◽

Prognostic Features ◽

Hpv Status

AbstractTreatment of locally advanced, unresectable head and neck squamous cell carcinoma (HNSCC) often yields only modest results with radiochemotherapy (RCT) as standard of care. Prognostic features related to outcome upon RCT might be highly valuable to improve treatment. Monocarboxylate transporters-1 and -4 (MCT1/MCT4) were evaluated as potential biomarkers. A cohort of HNSCC patients without signs for distant metastases was assessed eliciting 82 individuals eligible whereof 90% were diagnosed with locally advanced stage IV. Tumor specimens were stained for MCT1 and MCT4 in the cell membrane by immunohistochemistry. Obtained data were evaluated with respect to overall (OS) and progression-free survival (PFS). Protein expression of MCT1 and MCT4 in cell membrane was detected in 16% and 85% of the tumors, respectively. Expression of both transporters was not statistically different according to the human papilloma virus (HPV) status. Positive staining for MCT1 (n = 13, negative in n = 69) strongly worsened PFS with a hazard ratio (HR) of 3.1 (95%-confidence interval 1.6–5.7, p < 0.001). OS was likewise affected with a HR of 3.8 (2.0–7.3, p < 0.001). Multivariable Cox regression confirmed these findings. We propose MCT1 as a promising biomarker in HNSCC treated by primary RCT.

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