Fat accumulation in liver and muscle

94 Pages·2013·1.43 MB·English

by  Pisto, Pauliina

D OULU 2013
D 1202
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UNIVERSITY OF OULU P.O.B. 7500 FI-90014 UNIVERSITY OF OULU FINLAND
ACTA
A UNIVERSITATIS OULUENSIS
A C T A U N I V E R S I T A T I S O U L U E N S I S C
T
A
D
S E R I E S E D I T O R S MEDICA
Pauliina Pisto
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SCIENTIAE RERUM NATURALIUM
P FAT ACCUMULATION
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B Senior Assistant Jorma Arhippainen u
l
i
in IN LIVER AND MUSCLE
HUMANIORA
a

P
CUniversity Lecturer Santeri Palviainen i
s
t
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TECHNICA ASSOCIATION WITH ADIPOKINES AND
RISK OF CARDIOVASCULAR EVENTS
D Docent Hannu Heusala
MEDICA
E Professor Olli Vuolteenaho
SCIENTIAE RERUM SOCIALIUM
F University Lecturer Hannu Heikkinen
SCRIPTA ACADEMICA
G Director Sinikka Eskelinen
OECONOMICA
Professor Jari Juga
EDITOR IN CHIEF
Professor Olli Vuolteenaho
PUBLICATIONS EDITOR
Publications Editor Kirsti Nurkkala
UNIVERSITY OF OULU GRADUATE SCHOOL;
UNIVERSITY OF OULU, FACULTY OF MEDICINE,
INSTITUTE OF CLINICAL MEDICINE,
ISBN 978-952-62-0134-4 (Paperback)
DEPARTMENT OF INTERNAL MEDICINE;
ISBN 978-952-62-0135-1 (PDF) BIOCENTER OULU;
ISSN 0355-3221 (Print) CLINICAL RESEARCH CENTER,
ISSN 1796-2234 (Online) OULU UNIVERSITY HOSPITAL

ACTA UNIVERSITATIS OULUENSIS
D Medica 1202
PAULIINA PISTO
FAT ACCUMULATION IN LIVER AND
MUSCLE
Association with adipokines and risk of cardiovascular
events
Academic dissertation to be presented with the assent
of the Doctoral Training Committee of Health and
Biosciences of the University of Oulu for public
defence in Auditorium 101A of the Doctoral Training
Committee of Health and Biosciences (Aapistie 5 A),
on 7 June 2013, at 12 noon
UNIVERSITY OF OULU, OULU 2013
Copyright © 2013
Acta Univ. Oul. D 1202, 2013
Supervised by
Docent Olavi Ukkola
Professor Antero Kesäniemi
Doctor Merja Santaniemi
Reviewed by
Professor Antti Reunanen
Professor Jussi Pihlajamäki

ISBN 978-952-62-0134-4 (Paperback)
ISBN 978-952-62-0135-1 (PDF)
ISSN 0355-3221 (Printed)
ISSN 1796-2234 (Online)
Cover Design
Raimo Ahonen
JUVENES PRINT
TAMPERE 2013
Pisto, Pauliina, Fat accumulation in liver and muscle. Association with adipokines
and risk of cardiovascular events
University of Oulu Graduate School; University of Oulu, Faculty of Medicine, Institute of
Clinical Medicine, Department of Internal Medicine; Biocenter Oulu; Clinical Research Center,
Oulu University Hospital, P.O. Box 5000, FI-90014 University of Oulu, Finland
Acta Univ. Oul. D 1202, 2013
Oulu, Finland
Abstract
The prevalence of obesity is dramatically on the rise in the Western world. Obesity is associated
with several chronic diseases, including diabetes and cardiovascular disease (CVD). Non-
alcoholic fatty liver disease occurs when fat is ectopically stored in the liver. It is closely
associated with serious metabolic abnormalities. Non-alcoholic fatty liver disease ranges from
simple hepatic steatosis with no inflammation to hepatic steatosis with a necroinflammatory
component, which may lead to cirrhosis and liver failure. Adiponectin is an adipokine that is solely
secreted by adipocytes and has anti-inflammatory, antiatherogenic and insulin-sensitizing
properties. Adipose tissue inflammation contributes to reduced plasma adiponectin levels in
obesity leading to further metabolic complications. Adiponectin may be a mediator between
obesity and fat accumulation in the liver and skeletal muscle. Fatty liver may play a role in the
pathogenesis of CVD. Mortality data show that CVD as the cause of death accounts for almost half
of all deaths in Finland. Traditional risk factors for CVD are age, gender, smoking, high low-
density lipoprotein level, high blood pressure and diabetes.
The aim of the thesis was to investigate the mediators of fat accumulation in the liver and
skeletal muscle as well as the role of fatty liver in the future risk for CVD. If one considers the
peptide hormones, then adiponectin turned out to be the strongest independent indicator of the
brightness of the liver. In addition, an association between a low adiponectin concentration and
large muscle fiber size was observed, and this was not dependent on the amount of total fatness.
Furthermore, severe fatty liver increased the risk for cardiovascular events, predicted the risk for
death from all causes and death from CVD in a long follow-up. Insulin sensitivity seemed to play
a more dominant role in developing cardiovascular events.
In conclusion, this study demonstrates that adiponectin may have an important effect on fat
accumulation in the liver and skeletal muscle. Adiponectin could be a target when considering the
treatment and prevention of ectopic fat accumulation. Fatty liver seems to play a significant role
in developing cardiovascular event and mortality to CVD.
Keywords: adipokines, coronary disease, fatty liver, insulin resistance, lipid metabolism,
risk factors, skeletal muscle fiber, stroke

Pisto, Pauliina, Rasvan kertyminen maksaan ja lihakseen. Yhteys adipokiineihin ja
kardiovaskulaaritapahtumiin
Oulun yliopiston tutkijakoulu; Oulun yliopisto, Lääketieteellinen tiedekunta, Kliinisen
lääketieteen laitos, Sisätaudit; Biocenter Oulu; Kliinisen tutkimuksen keskus, Oulun
yliopistollinen sairaala, PL 5000, 90014 Oulun yliopisto
Acta Univ. Oul. D 1202, 2013
Oulu
Tiivistelmä
Lihavuus on kasvava ongelma länsimaissa. Lihavuudella on todettu olevan yhteyttä lukuisiin
kroonisiin sairauksiin, kuten diabetekseen ja sydän- ja verisuonitautiin. Ei-alkoholiperäinen ras-
vamaksa aiheutuu rasvan kertymisestä maksaan. Tilan on todettu liittyvän läheisesti vaikeisiin
aineenvaihdunnan häiriöihin. Ei-alkoholiperäinen rasvamaksa vaihtelee vakavuusasteeltaan
poikkeavasta rasvan kertymisestä tulehdukseen, joka voi edelleen johtaa kirroosiin ja maksan
toiminnan pettämiseen. Adiponektiini on pääasiassa rasvakudoksen erittämä hormoni, jolla on
tulehdusta hillitseviä, ateroskleroosilta suojaavia ja insuliinia herkistäviä ominaisuuksia. Rasva-
kudoksen tulehdustila myötävaikuttaa alentuneeseen adiponektiinipitoisuuteen, joka voi johtaa
vaikeutuneisiin aineenvaihdunnan häiriöihin. Adiponektiinin epäillään olevan välittäjäaine liha-
vuuden ja rasvamaksan ja lihaksensisäisen rasvan välillä. Rasvamaksan ja kardiovaskulaarisaira-
uksien välillä saattaa olla yhteys. Sydän- ja verisuonisairaudet aiheuttavat lähes puolet kuolemis-
ta Suomessa. Perinteisiä kardiovaskulaaritaudin riskitekijöitä ovat ikä, sukupuoli, tupakointi,
korkea LDL-kolesteroli, korkea verenpaine ja diabetes.
Tutkimuksemme tavoitteena oli selvittää maksan ja lihaksen rasvan kertymiseen myötävai-
kuttavia tekijöitä sekä rasvamaksan vaikutusta riskiin sairastua sydän- ja verisuonisairauksiin.
Tutkimuksessa havaittiin, että lihavuuteen liittyvistä hormoneista adiponektiini oli vahvin itse-
näinen myötävaikuttaja rasvamaksan kehittymisessä. Plasman alentunut adiponektiinipitoisuus
yhdistyi kasvaneeseen lihassolun kokoon riippumatta henkilöiden rasvakudoksen määrästä. Seu-
rantatutkimuksen mukaan vaikeasti rasvoittunut maksa lisäsi riskiä sairastua kardiovaskulaari-
tautiin, ennusti yleistä kuolemanriskiä ja kuolemaa kardiovaskulaaritautiin. Insuliiniherkkyydel-
lä näytti olevan merkittävä rooli sydän- ja verisuonitautitapahtumissa.
Tutkimus osoittaa, että adiponektiinillä saattaa olla keskeinen rooli rasvan kertymisessä mak-
saan ja lihakseen. Adiponektiini voi olla keskeinen tutkimuskohde kehiteltäessä hoitomuotoja ja
ehkäisymenetelmiä rasvakudoksen ulkopuolisen rasvan kertymiseen. Rasvamaksan rooli sairaa-
lahoitoon tai kuolemaan johtavissa ateroskleroottisissa tapahtumissa on ilmeinen.
Asiasanat: adipokiinit, aivohalvaus, insuliiniresistenssi, luurankolihassolu, rasva-
aineenvaihdunta, rasvamaksa, riskitekijät, sepelvaltimotauti

Acknowledgements
This thesis work was carried out in the Department of Internal Medicine, Institute
of Clinical Medicine, Biocenter Oulu, and Clinical research Center, Oulu
University Hospital. I wish to acknowledge the institutes for providing excellent
research facilities.
I would like to express my warmest gratitude to Docent Olavi Ukkola, MD,
PhD, and Professor Antero Kesäniemi, MD, PhD, for professional guidance and
for encouraging me in the field of science throughout the whole thesis work.
Olavi and Antero have provided outstanding working facilities and resources for
my thesis.
My third supervisor, Doctor Merja Santaniemi, PhD, deserves special thanks
for the indispensable support, never-ending patience and friendship. Merja has
always been available for scientific questions and conversations about everyday
life.
I express my warm thanks to my collaborators and co-authors. I am grateful
for Juha-Pekka Turpeinen, MD, MSc, and statistician Risto Bloigu, MSc, for
friendly collaboration. The official referees of this thesis, Professor Jussi
Pihlajamäki, MD, PhD, and Professor Antti Reunanen, MD, PhD, deserve
gratitude for their constructive criticism and inspiring comments. I wish to thank
Anna Vuolteenaho, MA, for the excellent revision of the language.
I am highly grateful to all the workmates in our research group and in CRC. I
wish to thank Meiju Saukko, MSc, and Elina Malo, MSc, for sharing thoughts
about science and life. Ms Heidi Häikiö and Ms Saija Kortetjärvi deserve thanks
for their skillful work in the laboratory. I warmly thank Secretary Marita
Koistinen for her help with several matters. Docent Tiina Hurskainen, PhD, is
thanked for providing good laboratory working facilities. Additionally, Anna-
Maria, Antti, Justiina, Tiia, Tuire, Malla, Saara and Sari deserve thanks for the
help and conversations. I wish to thank Tuija for sharing the dilemmas in the last
stage of the thesis.
I owe sincere gratitude to all my friends near and far. Elisa, Antti, Laura,
Sakke, Roosa, Maria, Kukka, Eeva, Hanna, Jonna and all my friends and relatives
who are not mentioned here: Thank you for the friendship and all the memorable
moments and discussions outside of science. I also thank my colleagues in
medical school for sharing their thoughts about medicine and everyday life during
these years. Markus deserves thanks for the statistical help.
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My deepest gratitude goes to my lovely family. Dad, thank you for giving me
a solid basis for my life and for everything you have done for me. Tommi, Leena-
Maija, Enni, Eero, Aapo, Hugo, Tuulia, Inka, Saila and Ilari, you mean the world
to me. It has been a privilege growing up with you. Mama, I miss you so much.
From the bottom of my heart, deepest thanks for the love and care. Kari, I wish to
thank you for the endless love, understanding and encouraging support during
these years. You gave me strength to complete this thesis.
I wish to acknowledge all the financial support given to this work by the
Research Council for Health of the Academy of Finland, the Finnish Foundation
for Cardiovascular Research and the Sigrid Juselius Foundation.
Oulu, April 10th 2013 Pauliina Pisto
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