Exercise increases myocardial free fatty acid oxidation in subjects with metabolic dysfunction-associated fatty liver disease

Jeyanthini Risikesan; Sara Heebøll; Indumathi Kumarathas; Kristian L. Funck; Esben Søndergaard; Rakel F. Johansen; Steffen Ringgaard; Lars P. Tolbod; Mogens Johannsen; Helle L. Kanstrup; Henning Grønbæk; Jan Frystyk; Lars C. Gormsen; Søren Nielsen

doi:10.1016/j.atherosclerosis.2023.03.015

Exercise increases myocardial free fatty acid oxidation in subjects with metabolic dysfunction-associated fatty liver disease

Jeyanthini Risikesan, Sara Heebøll, Indumathi Kumarathas, Kristian L. Funck, Esben Søndergaard, Rakel F. Johansen, Steffen Ringgaard, Lars P. Tolbod, Mogens Johannsen, Helle L. Kanstrup, Henning Grønbæk, Jan Frystyk, Lars C. Gormsen, Søren Nielsen^*

^*Kontaktforfatter

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

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Abstract

Background and aims: Metabolic dysfunction-associated fatty liver disease (MAFLD) is associated with dyslipidemia and may promote cardiac lipotoxicity. Myocardial free fatty acids (FFA) oxidation (MO_FFA) is normal in pre-diabetes, but reduced in heart failure. We hypothesized that during exercise MO_FFA, very low-density lipoprotein triglycerides (VLDL-TG) secretion, hepatic FFA utilization, and lactate production differ among obese subjects with and without MAFLD. Methods: Nine obese subjects with MAFLD and 8 matched subjects without MAFLD (Control) without a history of heart failure and cardiovascular disease were compared before and after 90-min exercise at 50% Peak oxygen consumption. Basal and exercise induced cardiac and hepatic FFA oxidation, uptake and re-esterification and VLDL-TG secretion were measured using [¹¹C]palmitate positron-emission tomography and [1–¹⁴C]VLDL-TG. Results: In the heart, increased MO_FFA was observed after exercise in MAFLD, whereas MO_FFA decreased in Control (basal vs exercise, MAFLD: 4.1 (0.8) vs 4.8 (0.8) μmol·100 ml⁻¹ min⁻¹; Control: 4.9 (1.8) vs 4.0 (1.1); μmol·100 ml⁻¹ min⁻¹, mean (SD), p < 0.048). Hepatic FFA fluxes were significantly lower in MAFLD than Control and increased ≈ two-fold in both groups. VLDL-TG secretion was 50% greater in MAFLD at rest and similarly suppressed during exercise. Plasma lactate increased significantly less in MAFLD than Control during exercise. Conclusions: Using robust tracer-techniques we found that obese subjects with MAFLD do not downregulate MO_FFA during exercise compared to Control, possibly due to diminished lactate supply. Hepatic FFA fluxes are significantly lower in MAFLD than Control, but increase similarly with exercise. VLDL-TG export remains greater in MAFLD compared to Control. Basal and post-exercise myocardial and hepatic FFA, VLDL-TG and lactate metabolism is abnormal in subjects with MAFLD compared to Control.

Originalsprog	Engelsk
Tidsskrift	Atherosclerosis
Vol/bind	372
Sider (fra-til)	10-18
ISSN	0021-9150
DOI	https://doi.org/10.1016/j.atherosclerosis.2023.03.015
Status	Udgivet - maj 2023

Bibliografisk note

Funding Information:
This study was supported by The Novo Nordic Foundation (grant numbers NNF18OC0031804 , NNF16OC0021406 ), The Independent Research Fund Denmark (grant number 8020-00420B ), Aarhus University and Steno Diabetes Centre Aarhus, Denmark. Funding sources had no involvement in any part of this study. All authors have read and approved the final manuscript.

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10.1016/j.atherosclerosis.2023.03.015Licens: CC BY

Open Access VersionForlagets udgivne version, 3,67 MBLicens: CC BY

Citationsformater

Risikesan, J., Heebøll, S., Kumarathas, I., Funck, K. L., Søndergaard, E., Johansen, R. F., Ringgaard, S., Tolbod, L. P., Johannsen, M., Kanstrup, H. L., Grønbæk, H., Frystyk, J., Gormsen, L. C., & Nielsen, S. (2023). Exercise increases myocardial free fatty acid oxidation in subjects with metabolic dysfunction-associated fatty liver disease. Atherosclerosis, 372, 10-18. https://doi.org/10.1016/j.atherosclerosis.2023.03.015

@article{e084453689364f6fa755746586bd1df6,

title = "Exercise increases myocardial free fatty acid oxidation in subjects with metabolic dysfunction-associated fatty liver disease",

abstract = "Background and aims: Metabolic dysfunction-associated fatty liver disease (MAFLD) is associated with dyslipidemia and may promote cardiac lipotoxicity. Myocardial free fatty acids (FFA) oxidation (MOFFA) is normal in pre-diabetes, but reduced in heart failure. We hypothesized that during exercise MOFFA, very low-density lipoprotein triglycerides (VLDL-TG) secretion, hepatic FFA utilization, and lactate production differ among obese subjects with and without MAFLD. Methods: Nine obese subjects with MAFLD and 8 matched subjects without MAFLD (Control) without a history of heart failure and cardiovascular disease were compared before and after 90-min exercise at 50% Peak oxygen consumption. Basal and exercise induced cardiac and hepatic FFA oxidation, uptake and re-esterification and VLDL-TG secretion were measured using [11C]palmitate positron-emission tomography and [1–14C]VLDL-TG. Results: In the heart, increased MOFFA was observed after exercise in MAFLD, whereas MOFFA decreased in Control (basal vs exercise, MAFLD: 4.1 (0.8) vs 4.8 (0.8) μmol·100 ml−1 min−1; Control: 4.9 (1.8) vs 4.0 (1.1); μmol·100 ml−1 min−1, mean (SD), p < 0.048). Hepatic FFA fluxes were significantly lower in MAFLD than Control and increased ≈ two-fold in both groups. VLDL-TG secretion was 50% greater in MAFLD at rest and similarly suppressed during exercise. Plasma lactate increased significantly less in MAFLD than Control during exercise. Conclusions: Using robust tracer-techniques we found that obese subjects with MAFLD do not downregulate MOFFA during exercise compared to Control, possibly due to diminished lactate supply. Hepatic FFA fluxes are significantly lower in MAFLD than Control, but increase similarly with exercise. VLDL-TG export remains greater in MAFLD compared to Control. Basal and post-exercise myocardial and hepatic FFA, VLDL-TG and lactate metabolism is abnormal in subjects with MAFLD compared to Control.",

keywords = "Exercise, Fatty liver disease, FFA, Free fatty acids, Lipoprotein metabolism, MAFLD, PET palmitate Tracer, PET scanning, VLDL-TG tracer, VLDL-Triglycerides, Humans, Heart Failure/complications, Lipid Metabolism, Triglycerides, Lipoproteins, VLDL, Liver/metabolism, Fatty Acids, Nonesterified, Obesity/complications, Non-alcoholic Fatty Liver Disease/complications",

author = "Jeyanthini Risikesan and Sara Heeb{\o}ll and Indumathi Kumarathas and Funck, {Kristian L.} and Esben S{\o}ndergaard and Johansen, {Rakel F.} and Steffen Ringgaard and Tolbod, {Lars P.} and Mogens Johannsen and Kanstrup, {Helle L.} and Henning Gr{\o}nb{\ae}k and Jan Frystyk and Gormsen, {Lars C.} and S{\o}ren Nielsen",

note = "Publisher Copyright: {\textcopyright} 2023 The Authors",

year = "2023",

month = may,

doi = "10.1016/j.atherosclerosis.2023.03.015",

language = "English",

volume = "372",

pages = "10--18",

journal = "Atherosclerosis",

issn = "0021-9150",

publisher = "Elsevier",

}

Risikesan, J, Heebøll, S, Kumarathas, I, Funck, KL, Søndergaard, E, Johansen, RF, Ringgaard, S, Tolbod, LP, Johannsen, M, Kanstrup, HL, Grønbæk, H, Frystyk, J, Gormsen, LC & Nielsen, S 2023, 'Exercise increases myocardial free fatty acid oxidation in subjects with metabolic dysfunction-associated fatty liver disease', Atherosclerosis, bind 372, s. 10-18. https://doi.org/10.1016/j.atherosclerosis.2023.03.015

TY - JOUR

T1 - Exercise increases myocardial free fatty acid oxidation in subjects with metabolic dysfunction-associated fatty liver disease

AU - Risikesan, Jeyanthini

AU - Heebøll, Sara

AU - Kumarathas, Indumathi

AU - Funck, Kristian L.

AU - Søndergaard, Esben

AU - Johansen, Rakel F.

AU - Ringgaard, Steffen

AU - Tolbod, Lars P.

AU - Johannsen, Mogens

AU - Kanstrup, Helle L.

AU - Grønbæk, Henning

AU - Frystyk, Jan

AU - Gormsen, Lars C.

AU - Nielsen, Søren

PY - 2023/5

Y1 - 2023/5

N2 - Background and aims: Metabolic dysfunction-associated fatty liver disease (MAFLD) is associated with dyslipidemia and may promote cardiac lipotoxicity. Myocardial free fatty acids (FFA) oxidation (MOFFA) is normal in pre-diabetes, but reduced in heart failure. We hypothesized that during exercise MOFFA, very low-density lipoprotein triglycerides (VLDL-TG) secretion, hepatic FFA utilization, and lactate production differ among obese subjects with and without MAFLD. Methods: Nine obese subjects with MAFLD and 8 matched subjects without MAFLD (Control) without a history of heart failure and cardiovascular disease were compared before and after 90-min exercise at 50% Peak oxygen consumption. Basal and exercise induced cardiac and hepatic FFA oxidation, uptake and re-esterification and VLDL-TG secretion were measured using [11C]palmitate positron-emission tomography and [1–14C]VLDL-TG. Results: In the heart, increased MOFFA was observed after exercise in MAFLD, whereas MOFFA decreased in Control (basal vs exercise, MAFLD: 4.1 (0.8) vs 4.8 (0.8) μmol·100 ml−1 min−1; Control: 4.9 (1.8) vs 4.0 (1.1); μmol·100 ml−1 min−1, mean (SD), p < 0.048). Hepatic FFA fluxes were significantly lower in MAFLD than Control and increased ≈ two-fold in both groups. VLDL-TG secretion was 50% greater in MAFLD at rest and similarly suppressed during exercise. Plasma lactate increased significantly less in MAFLD than Control during exercise. Conclusions: Using robust tracer-techniques we found that obese subjects with MAFLD do not downregulate MOFFA during exercise compared to Control, possibly due to diminished lactate supply. Hepatic FFA fluxes are significantly lower in MAFLD than Control, but increase similarly with exercise. VLDL-TG export remains greater in MAFLD compared to Control. Basal and post-exercise myocardial and hepatic FFA, VLDL-TG and lactate metabolism is abnormal in subjects with MAFLD compared to Control.

AB - Background and aims: Metabolic dysfunction-associated fatty liver disease (MAFLD) is associated with dyslipidemia and may promote cardiac lipotoxicity. Myocardial free fatty acids (FFA) oxidation (MOFFA) is normal in pre-diabetes, but reduced in heart failure. We hypothesized that during exercise MOFFA, very low-density lipoprotein triglycerides (VLDL-TG) secretion, hepatic FFA utilization, and lactate production differ among obese subjects with and without MAFLD. Methods: Nine obese subjects with MAFLD and 8 matched subjects without MAFLD (Control) without a history of heart failure and cardiovascular disease were compared before and after 90-min exercise at 50% Peak oxygen consumption. Basal and exercise induced cardiac and hepatic FFA oxidation, uptake and re-esterification and VLDL-TG secretion were measured using [11C]palmitate positron-emission tomography and [1–14C]VLDL-TG. Results: In the heart, increased MOFFA was observed after exercise in MAFLD, whereas MOFFA decreased in Control (basal vs exercise, MAFLD: 4.1 (0.8) vs 4.8 (0.8) μmol·100 ml−1 min−1; Control: 4.9 (1.8) vs 4.0 (1.1); μmol·100 ml−1 min−1, mean (SD), p < 0.048). Hepatic FFA fluxes were significantly lower in MAFLD than Control and increased ≈ two-fold in both groups. VLDL-TG secretion was 50% greater in MAFLD at rest and similarly suppressed during exercise. Plasma lactate increased significantly less in MAFLD than Control during exercise. Conclusions: Using robust tracer-techniques we found that obese subjects with MAFLD do not downregulate MOFFA during exercise compared to Control, possibly due to diminished lactate supply. Hepatic FFA fluxes are significantly lower in MAFLD than Control, but increase similarly with exercise. VLDL-TG export remains greater in MAFLD compared to Control. Basal and post-exercise myocardial and hepatic FFA, VLDL-TG and lactate metabolism is abnormal in subjects with MAFLD compared to Control.

KW - Exercise

KW - Fatty liver disease

KW - FFA

KW - Free fatty acids

KW - Lipoprotein metabolism

KW - MAFLD

KW - PET palmitate Tracer

KW - PET scanning

KW - VLDL-TG tracer

KW - VLDL-Triglycerides

KW - Humans

KW - Heart Failure/complications

KW - Lipid Metabolism

KW - Triglycerides

KW - Lipoproteins, VLDL

KW - Liver/metabolism

KW - Fatty Acids, Nonesterified

KW - Obesity/complications

KW - Non-alcoholic Fatty Liver Disease/complications

U2 - 10.1016/j.atherosclerosis.2023.03.015

DO - 10.1016/j.atherosclerosis.2023.03.015

M3 - Journal article

C2 - 37011565

AN - SCOPUS:85151430142

SN - 0021-9150

VL - 372

SP - 10

EP - 18

JO - Atherosclerosis

JF - Atherosclerosis

ER -

Exercise increases myocardial free fatty acid oxidation in subjects with metabolic dysfunction-associated fatty liver disease

Abstract

Bibliografisk note

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