4 research outputs found
The outcome of boosting mitochondrial activity in alcohol-associated liver disease is organ-dependent.
BACKGROUND AND AIMS
Alcohol-associated liver disease (ALD) accounts for 70% of liver-related deaths in Europe, with no effective approved therapies. Although mitochondrial dysfunction is one of the earliest manifestations of alcohol-induced injury, restoring mitochondrial activity remains a problematic strategy due to oxidative stress. Here, we identify methylation-controlled J protein (MCJ) as a mediator for ALD progression and hypothesize that targeting MCJ may help in recovering mitochondrial fitness without collateral oxidative damage.
APPROACH AND RESULTS
C57BL/6 mice [wild-type (Wt)] Mcj knockout and Mcj liver-specific silencing (MCJ-LSS) underwent the NIAAA dietary protocol (Lieber-DeCarli diet containing 5% (vol/vol) ethanol for 10 days, plus a single binge ethanol feeding at day 11). To evaluate the impact of a restored mitochondrial activity in ALD, the liver, gut, and pancreas were characterized, focusing on lipid metabolism, glucose homeostasis, intestinal permeability, and microbiota composition. MCJ, a protein acting as an endogenous negative regulator of mitochondrial respiration, is downregulated in the early stages of ALD and increases with the severity of the disease. Whole-body deficiency of MCJ is detrimental during ALD because it exacerbates the systemic effects of alcohol abuse through altered intestinal permeability, increased endotoxemia, and dysregulation of pancreatic function, which overall worsens liver injury. On the other hand, liver-specific Mcj silencing prevents main ALD hallmarks, that is, mitochondrial dysfunction, steatosis, inflammation, and oxidative stress, as it restores the NAD + /NADH ratio and SIRT1 function, hence preventing de novo lipogenesis and improving lipid oxidation.
CONCLUSIONS
Improving mitochondrial respiration by liver-specific Mcj silencing might become a novel therapeutic approach for treating ALD.This work was supported by grants from Ministerio de
Ciencia e Innovación, Programa Retos-Colaboración
RTC2019-007125-1 (for Jorge Simon and Maria Luz
Martinez-Chantar); Ministerio de Economía, Industria y
Competitividad, Retos a la Sociedad AGL2017-
86927R (for F.M.); Instituto de Salud Carlos III,
Proyectos de Investigación en Salud DTS20/00138
and DTS21/00094 (for Jorge Simon and Maria Luz
Martinez-Chantar, and Asis Palazon. respectively);
Instituto de Salud Carlos III, Fondo de Investigaciones
Sanitarias co-founded by European Regional
Development Fund/European Social Fund, “Investing
in your future” PI19/00819, “Una manera de
hacer Europa” FIS PI20/00765, and PI21/01067 (for
Jose J. G. Marin., Pau Sancho-Bru,. and Mario F.
Fraga respectively); Departamento de Industria del
Gobierno Vasco (for Maria Luz Martinez-Chantar);
Asturias Government (PCTI) co-funding 2018-2023/
FEDER IDI/2021/000077 (for Mario F. Fraga.);
Ministerio de Ciencia, Innovación y Universidades
MICINN: PID2020-117116RB-I00, CEX2021-001136-S
PID2020-117941RB-I00, PID2020-11827RB-I00 and
PID2019-107956RA-100 integrado en el Plan Estatal
de Investigación Científica y Técnica y Innovación,
cofinanciado con Fondos FEDER (for Maria Luz Martinez-Chantar, Francisco J Cubero., Yulia A Nevzorova
and Asis Palazon); Ayudas Ramón y Cajal de la Agencia
Estatal de Investigación RY2013-13666 and RYC2018-
024183-I (for Leticia Abecia and Asis Palazon); European Research Council Starting Grant 804236 NEXTGEN-IO (for Asis Palazon); The German Research
Foundation SFB/TRR57/P04, SFB1382-403224013/
A02 and DFG NE 2128/2-1 (for Francisco J Cubero
and Yulia A Nevzorova); National Institute of Health (NIH)/National Institute of Alcohol Abuse and Alcoholism
(NIAAA) 1U01AA026972-01 (For Pau Sancho-Bru);
Junta de Castilla y León SA074P20 (for Jose J. G.
Marin); Junta de Andalucía, Grupo PAIDI BIO311 (for
Franz Martin); CIBERER Acciones Cooperativas y
Complementarias Intramurales ACCI20-35 (for Mario F.
Fraga); Ministerio de Educación, Cultura y Deporte
FPU17/04992 (for Silvia Ariño); Fundació Marato TV3
201916-31 (for Jose J. G. Marin.); Ainize Pena-Cearra is
a fellow of the University of the Basque Country (UPV/
EHU); BIOEF (Basque Foundation for Innovation and
Health Research); Asociación Española contra el Cáncer
(Maria Luz Martinez-Chantar and Teresa C. Delgado.);
Fundación Científica de la Asociación Española Contra
el Cáncer (AECC Scientific Foundation) Rare Tumor
Calls 2017 (for Maria Luz Martinez-Chantar); La Caixa
Foundation Program (for Maria Luz Martinez-Chantar);
Proyecto Desarrollo Tecnologico CIBERehd (for Maria
Luz Martinez-Chantar); Ciberehd_ISCIII_MINECO is
funded by the Instituto de Salud Carlos III.S
Inhibition of carnitine palmitoyltransferase 1A in hepatic stellate cells protects against fibrosis
One of the most common types of fibrotic liver occurs in patients with non-alcoholic fatty liver disease (NAFLD), which may develop into non-alcoholic steatohepatitis (NASH). Hepatic stellate cells (HSCs) are the primary fibrogenic cell type activated following liver injury, moving from a quiescent phenotype rich in vitamin A into activated myofibroblast-like cells with proliferative and migratory properties.This work has been supported by grants from FEDER/Ministerio de Ciencia, Innovación y Universidades-Agencia Estatal de Investigación (DS and LH: SAF2017-83813-C3-1-R; MLMC: RTC2019-007125-1; CD: BFU2017-87721; ML: RTI2018–101840-B-I00; RN: RTI2018-099413-B-I00 and RED2018-102379-T; MLMC: SAF2017-87301-R; TCD: RTI2018-096759-A-100), Xunta de Galicia (ML: 2016-PG068; RN: 2015-CP080 and 2016-PG057), Fundación BBVA (RN and MLM), Proyectos Investigación en Salud (MLMC: DTS20/00138), Sistema Universitario Vasco (PA: IT971-16); Fundacion Araucaria (ML and RN), Gilead Sciences International Research Scholars Program in Liver Disease (MVR), Marató TV3 Foundation (DS: 201627), Government of Catalonia (DS: 2017SGR278) and European Foundation for the Study of Diabetes (RN). This research also received funding from the European Community’s H2020 Framework Programme (ERC Synergy Grant-2019-WATCH- 810331, to RN, VP and MS). Centro de Investigación Biomédica en Red (CIBER) de Fisiopatología de la Obesidad y Nutrición (CIBERobn), Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Hepáticas y Digestivas (CIBERehd). CIBERobn and CIBERehd are initiatives of the Instituto de Salud Carlos III (ISCIII) of Spain which is supported by FEDER funds. We thank MINECO for the Severo Ochoa Excellence Accreditation to CIC bioGUNE (SEV-2016-0644)S