RRC ID 72135
Author Ishihama S, Yoshida S, Yoshida T, Mori Y, Ouchi N, Eguchi S, Sakaguchi T, Tsuda T, Kato K, Shimizu Y, Ohashi K, Okumura T, Bando YK, Yagyu H, Wettschureck N, Kubota N, Offermanns S, Kadowaki T, Murohara T, Takefuji M.
Title LPL/AQP7/GPD2 promotes glycerol metabolism under hypoxia and prevents cardiac dysfunction during ischemia.
Journal FASEB J
Abstract In the heart, fatty acid is a major energy substrate to fuel contraction under aerobic conditions. Ischemia downregulates fatty acid metabolism to adapt to the limited oxygen supply, making glucose the preferred substrate. However, the mechanism underlying the myocardial metabolic shift during ischemia remains unknown. Here, we show that lipoprotein lipase (LPL) expression in cardiomyocytes, a principal enzyme that converts triglycerides to free fatty acids and glycerol, increases during myocardial infarction (MI). Cardiomyocyte-specific LPL deficiency enhanced cardiac dysfunction and apoptosis following MI. Deficiency of aquaporin 7 (AQP7), a glycerol channel in cardiomyocytes, increased the myocardial infarct size and apoptosis in response to ischemia. Ischemic conditions activated glycerol-3-phosphate dehydrogenase 2 (GPD2), which converts glycerol-3-phosphate into dihydroxyacetone phosphate to facilitate adenosine triphosphate (ATP) synthesis from glycerol. Conversely, GPD2 deficiency exacerbated cardiac dysfunction after acute MI. Moreover, cardiomyocyte-specific LPL deficiency suppressed the effectiveness of peroxisome proliferator-activated receptor alpha (PPARα) agonist treatment for MI-induced cardiac dysfunction. These results suggest that LPL/AQP7/GPD2-mediated glycerol metabolism plays an important role in preventing myocardial ischemia-related damage.
Volume 35(12)
Pages e22048
Published 2021-12-1
DOI 10.1096/fj.202100882R
PMID 34807469
MeSH Animals Aquaporins / genetics Aquaporins / metabolism* Cardiomyopathies / etiology Cardiomyopathies / metabolism Cardiomyopathies / pathology Cardiomyopathies / prevention & control* Glycerol / metabolism* Glycerolphosphate Dehydrogenase / genetics Glycerolphosphate Dehydrogenase / metabolism* Hypoxia / physiopathology* Ischemia / etiology Ischemia / metabolism Ischemia / pathology Ischemia / prevention & control* Lipoprotein Lipase / physiology* Male Mice Mice, Knockout Mitochondrial Proteins / genetics Mitochondrial Proteins / metabolism*
IF 4.966
Mice RBRC06294