Research Article| Volume 78, ISSUE 1, P180-190, January 2023

Partial MCT1 invalidation protects against diet-induced non-alcoholic fatty liver disease and the associated brain dysfunction

Open AccessPublished:August 19, 2022DOI:


      • Diet-induced NAFLD and associated systemic alterations result in behavioural changes and low-grade brain tissue hypoxia.
      • Brain hypoxia is likely linked to the induced low-grade brain inflammation, as well as cerebrovascular, glial, and metabolic alterations.
      • Mct1 haploinsufficient mice are protected from NAFLD and detrimental cerebral alterations.
      • MCT1 is a potential novel therapeutic target for preventing and/or treating NAFLD and the associated multifactorial encephalopathy.

      Background & Aims

      Non-alcoholic fatty liver disease (NAFLD) has been associated with mild cerebral dysfunction and cognitive decline, although the exact pathophysiological mechanism remains ambiguous. Using a diet-induced model of NAFLD and monocarboxylate transporter-1 (Mct1+/−) haploinsufficient mice, which resist high-fat diet-induced hepatic steatosis, we investigated the hypothesis that NAFLD leads to an encephalopathy by altering cognition, behaviour, and cerebral physiology. We also proposed that global MCT1 downregulation offers cerebral protection.


      Behavioural tests were performed in mice following 16 weeks of control diet (normal chow) or high-fat diet with high fructose/glucose in water. Tissue oxygenation, cerebrovascular reactivity, and cerebral blood volume were monitored under anaesthesia by multispectral optoacoustic tomography and optical fluorescence. Cortical mitochondrial oxygen consumption and respiratory capacities were measured using ex vivo high-resolution respirometry. Microglial and astrocytic changes were evaluated by immunofluorescence and 3D reconstructions. Body composition was assessed using EchoMRI, and liver steatosis was confirmed by histology.


      NAFLD concomitant with obesity is associated with anxiety- and depression-related behaviour. Low-grade brain tissue hypoxia was observed, likely attributed to the low-grade brain inflammation and decreased cerebral blood volume. It is also accompanied by microglial and astrocytic morphological and metabolic alterations (higher oxygen consumption), suggesting the early stages of an obesogenic diet-induced encephalopathy. Mct1 haploinsufficient mice, despite fat accumulation in adipose tissue, were protected from NAFLD and associated cerebral alterations.


      This study provides evidence of compromised brain health in obesity and NAFLD, emphasising the importance of the liver–brain axis. The protective effect of Mct1 haploinsufficiency points to this protein as a novel therapeutic target for preventing and/or treating NAFLD and the associated brain dysfunction.

      Impact and implications

      This study is focused on unravelling the pathophysiological mechanism by which cerebral dysfunction and cognitive decline occurs during NAFLD and exploring the potential of monocarboxylate transporter-1 (MCT1) as a novel preventive or therapeutic target. Our findings point to NAFLD as a serious health risk and its adverse impact on the brain as a potential global health system and economic burden. These results highlight the utility of Mct1 transgenic mice as a model for NAFLD and associated brain dysfunction and call for systematic screening by physicians for early signs of psychological symptoms, and an awareness by individuals at risk of these potential neurological effects. This study is expected to bring attention to the need for early diagnosis and treatment of NAFLD, while having a direct impact on policies worldwide regarding the health risk associated with NAFLD, and its prevention and treatment.

      Graphical abstract


      Linked Article

      • Reply to: “Is NAFLD a key driver of brain dysfunction?”
        Journal of HepatologyVol. 78Issue 4
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          We thank Sandforth and colleagues for their interest in our study.1,2 In their letter to the editor, Sandforth et al., refer to “body weight data missing in the report”. However, they do not indicate what would be the added value of reporting such data. Body weight was determined weekly, but these data were not presented as considered not of interest in the present context. More relevant to the focus of the article are the differences in fat mass. We would like to kindly point to Fig. 2A-B in our original paper, which depicts % fat mass and lean mass assessed by EchoMRI at the end of the 16-week feeding protocol, the time point at which all experiments were performed.
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      • Is NAFLD a key driver of brain dysfunction?
        Journal of HepatologyVol. 78Issue 4
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          We read with great interest the spectacular work of Hadjihambi and colleagues, published in August 2022 online ahead of print in the Journal.1 The authors aimed to establish the role of non-alcoholic fatty liver disease (NAFLD) in the development of brain dysfunction. To establish this role, the authors used a mouse model that they generated more than 10 years ago,2 monocarboxylate transporter-1 haploinsufficient (Mct1+/−) mice. MCT1 or SLC16A1 is a carrier of short-chain fatty acids, ketone bodies, and lactate in several tissues, including the liver, brain and adipose tissue, playing an important role in energy homeostasis in health and disease, including obesity, type 2 diabetes and cancer.
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        • Byrne C.D.
        • Targher G.
        NAFLD: a multisystem disease.
        J Hepatol. 2015; 62: S47-S64
        • Sanyal A.J.
        • Van Natta M.L.
        • Clark J.
        • Neuschwander-Tetri B.A.
        • Diehl A.
        • Dasarathy S.
        • et al.
        Prospective study of outcomes in adults with nonalcoholic fatty liver disease.
        N Engl J Med. 2021; 385: 1559-1569
        • Kanoski S.E.
        • Davidson T.L.
        Different patterns of memory impairments accompany short- and longer-term maintenance on a high-energy diet.
        J Exp Psychol Anim Behav Process. 2010; 36: 313-319
        • Filipović B.
        • Marković O.
        • Ðurić V.
        • Filipović B.
        Cognitive changes and brain volume reduction in patients with nonalcoholic fatty liver disease.
        Can J Gastroenterol Hepatol. 2018; 20189638797
        • Takahashi A.
        • Kono S.
        • Wada A.
        • Oshima S.
        • Abe K.
        • Imaizumi H.
        • et al.
        Reduced brain activity in female patients with non-alcoholic fatty liver disease as measured by near-infrared spectroscopy.
        PLoS One. 2017; 12e0174169
        • Colognesi M.
        • Gabbia D.
        • De Martin S.
        Depression and cognitive impairment-extrahepatic manifestations of NAFLD and NASH.
        Biomedicines. 2020; 8: 229
        • VanWagner L.B.
        • Terry J.G.
        • Chow L.S.
        • Alman A.C.
        • Kang H.
        • Ingram K.H.
        • et al.
        Nonalcoholic fatty liver disease and measures of early brain health in middle-aged adults: the CARDIA study.
        Obesity (Silver Spring). 2017; 25: 642-651
        • Kjærgaard K.
        • Mikkelsen A.C.D.
        • Wernberg C.W.
        • Grønkjær L.L.
        • Eriksen P.L.
        • Damholdt M.F.
        • et al.
        Cognitive dysfunction in non-alcoholic fatty liver disease – current knowledge, mechanisms and perspectives.
        J Clin Med. 2021; 10: 673
        • Hosford P.S.
        • Gourine A.V.
        What is the key mediator of the neurovascular coupling response?.
        Neurosci Biobehav Rev. 2019; 96: 174-181
        • Raichle M.E.
        The pathophysiology of brain ischemia.
        Ann Neurol. 1983; 13: 2-10
        • Halder S.K.
        • Milner R.
        Hypoxia in multiple sclerosis; is it the chicken or the egg?.
        Brain. 2021; 144: 402-410
        • Jiyeon O.
        • Cho H.-J.
        • Hong S.H.
        • Kim I.K.
        • Suk K.
        Hypoxia as an initiator of neuroinflammation: microglial connections.
        Curr Neuropharmacol. 2005; 3: 183-191
        • DiSabato D.J.
        • Quan N.
        • Godbout J.P.
        Neuroinflammation: the devil is in the details.
        J Neurochem. 2016; 139: 136-153
        • Moreno-Navarrete J.M.
        • Blasco G.
        • Puig J.
        • Biarnés C.
        • Rivero M.
        • Gich J.
        • et al.
        Neuroinflammation in obesity: circulating lipopolysaccharide-binding protein associates with brain structure and cognitive performance.
        Int J Obes (Lond). 2017; 41: 1627-1635
        • Pierre K.
        • Pellerin L.
        Monocarboxylate transporters in the central nervous system: distribution, regulation and function.
        J Neurochem. 2005; 94: 1-14
        • Carneiro L.
        • Asrih M.
        • Repond C.
        • Sempoux C.
        • Stehle J.C.
        • Leloup C.
        • et al.
        AMPK activation caused by reduced liver lactate metabolism protects against hepatic steatosis in MCT1 haploinsufficient mice.
        Mol Metab. 2017; 6: 1625-1633
        • Lengacher S.
        • Nehiri-Sitayeb T.
        • Steiner N.
        • Carneiro L.
        • Favrod C.
        • Preitner F.
        • et al.
        Resistance to diet-induced obesity and associated metabolic perturbations in haploinsufficient monocarboxylate transporter 1 mice.
        PLoS One. 2013; 8e82505
        • Percie du Sert N.
        • Hurst V.
        • Ahluwalia A.
        • Alam S.
        • Avey M.T.
        • Baker M.
        • et al.
        The ARRIVE guidelines 2.0: updated guidelines for reporting animal research.
        PLoS Biol. 2020; 18e3000410
        • Sitar-Taut A.V.
        • Cozma A.
        • Fodor A.
        • Coste S.C.
        • Orasan O.H.
        • Negrean V.
        • et al.
        New insights on the relationship between leptin, ghrelin, and leptin/ghrelin ratio enforced by body mass index in obesity and diabetes.
        Biomedicines. 2021; 9: 1657
        • Leyh J.
        • Winter K.
        • Reinicke M.
        • Ceglarek U.
        • Bechmann I.
        • Landmann J.
        Long-term diet-induced obesity does not lead to learning and memory impairment in adult mice.
        PLoS One. 2021; 16e0257921
        • Xia G.
        • Han Y.
        • Meng F.
        • He Y.
        • Srisai D.
        • Farias M.
        • et al.
        Reciprocal control of obesity and anxiety-depressive disorder via a GABA and serotonin neural circuit.
        Mol Psychiatry. 2021; 26: 2837-2853
        • Xiao J.
        • Lim L.K.E.
        • Ng C.H.
        • Tan D.J.H.
        • Lim W.H.
        • Ho C.S.H.
        • et al.
        Is fatty liver associated with depression? A meta-analysis and systematic review on the prevalence, risk factors, and outcomes of depression and non-alcoholic fatty liver disease.
        Front Med (Lausanne). 2021; 8691696
        • Luci C.
        • Bourinet M.
        • Leclère P.S.
        • Anty R.
        • Gual P.
        Chronic inflammation in non-alcoholic steatohepatitis: molecular mechanisms and therapeutic strategies.
        Front Endocrinol (Lausanne). 2020; 11597648
        • Dorfman M.D.
        • Thaler J.P.
        Hypothalamic inflammation and gliosis in obesity.
        Curr Opin Endocrinol Diabetes Obes. 2015; 22: 325-330
        • Balzano T.
        • Forteza J.
        • Molina P.
        • Giner J.
        • Monzó A.
        • Sancho-Jiménez J.
        • et al.
        The cerebellum of patients with steatohepatitis shows lymphocyte infiltration, microglial activation and loss of purkinje and granular neurons.
        Sci Rep. 2018; 8: 3004
        • Norden D.M.
        • Fenn A.M.
        • Dugan A.
        • Godbout J.P.
        TGFβ produced by IL-10 redirected astrocytes attenuates microglial activation.
        Glia. 2014; 62: 881-895
        • Ding X.
        • Yan Y.
        • Li X.
        • Li K.
        • Ciric B.
        • Yang J.
        • et al.
        Silencing IFN-γ binding/signaling in astrocytes versus microglia leads to opposite effects on central nervous system autoimmunity.
        J Immunol. 2015; 194: 4251-4264
        • Guillemot-Legris O.
        • Muccioli G.G.
        Obesity-induced neuroinflammation: beyond the hypothalamus.
        Trends Neurosci. 2017; 40: 237-253
        • Pellerin L.
        • Pellegri G.
        • Martin J.L.
        • Magistretti P.J.
        Expression of monocarboxylate transporter mRNAs in mouse brain: support for a distinct role of lactate as an energy substrate for the neonatal vs. adult brain.
        Proc Natl Acad Sci U S A. 1998; 95: 3990-3995
        • Kong L.
        • Wang Z.
        • Liang X.
        • Wang Y.
        • Gao L.
        • Ma C.
        Monocarboxylate transporter 1 promotes classical microglial activation and pro-inflammatory effect via 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase 3.
        J Neuroinflammation. 2019; 16: 240
        • Moreira T.J.
        • Pierre K.
        • Maekawa F.
        • Repond C.
        • Cebere A.
        • Liljequist S.
        • et al.
        Enhanced cerebral expression of MCT1 and MCT2 in a rat ischemia model occurs in activated microglial cells.
        J Cereb Blood Flow Metab. 2009; 29: 1273-1283
        • Perry V.H.
        The influence of systemic inflammation on inflammation in the brain: implications for chronic neurodegenerative disease.
        Brain Behav Immun. 2004; 18: 407-413
        • Mukandala G.
        • Tynan R.
        • Lanigan S.
        • O'Connor J.J.
        The effects of hypoxia and inflammation on synaptic signaling in the CNS.
        Brain Sci. 2016; 6: 6
        • Lombardi R.
        • Fargion S.
        • Fracanzani A.L.
        Brain involvement in non-alcoholic fatty liver disease (NAFLD): a systematic review.
        Dig Liver Dis. 2019; 51: 1214-1222
        • Institoris A.
        • Gordon G.R.
        A tense relationship between capillaries and pericytes.
        Nat Neurosci. 2021; 24: 615-617
        • Laferriere C.A.
        • Pang D.S.
        Review of intraperitoneal injection of sodium pentobarbital as a method of euthanasia in laboratory rodents.
        J Am Assoc Lab Anim Sci. 2020; 59: 254-263
        • Halestrap A.P.
        • Price N.T.
        The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation.
        Biochem J. 1999; 343: 281-299
        • Weiss H.J.
        • Angiari S.
        Metabolite transporters as regulators of immunity.
        Metabolites. 2020; 10: 418
        • Perez-Escuredo J.
        • Van Hée V.F.
        • Sboarina M.
        • Falces J.
        • Payen V.L.
        • Pellerin L.
        • et al.
        Monocarboxylate transporters in the brain and in cancer.
        Biochim Biophys Acta. 2016; 1863: 2481-2497
        • Elizondo-Vega R.
        • Cortes-Campos C.
        • Barahona M.J.
        • Oyarce K.A.
        • Carril C.A.
        • García-Robles M.A.
        The role of tanycytes in hypothalamic glucosensing.
        J Cell Mol Med. 2015; 19: 1471-1482
        • Geller S.
        • Arribat Y.
        • Netzahualcoyotzi C.
        • Lagarrigue S.
        • Carneiro L.
        • Zhang L.
        • et al.
        Tanycytes regulate lipid homeostasis by sensing free fatty acids and signaling to key hypothalamic neuronal populations via FGF21 secretion.
        Cell Metab. 2019; 30: 833-844.e7
        • Hadjihambi A.
        Cerebrovascular alterations in NAFLD: is it increasing our risk of Alzheimer's disease?.
        Anal Biochem. 2021; 636114387