Defective fatty acid uptake in the spontaneously hypertensive rat is a primary determinant of altered glucose metabolism, hyperinsulinemia, and myocardial hypertrophy.
Genetic linkage studies implicated deficiency of CD36, a membrane fatty acid (FA) transporter, in the hypertriglyceridemia and hyperinsulinemia of the spontaneously hypertensive rat (SHR). In this study we determined whether loss of CD36 function in FA uptake is a primary determinant of the SHR phenotype. In vivo, tissue distribution of iodinated, poorly oxidized beta-methyliodophenyl pentadecanoic acid (BMIPP) was examined 2 h after its intravenous injection. Fatty acid transport was also measured in vitro over 20 to 120 s in isolated adipocytes and cardiomyocytes obtained from SHR and from a congenic line (SHRchr4) that incorporates a piece of chromosome 4 containing wild-type CD36. SHR heart and adipose tissue exhibited defects in FA uptake and in conversion of diglycerides to triglycerides that are similar to those observed in the CD36 null mouse. However, a key difference in SHR tissues is that fatty acid oxidation is much more severely impaired than fatty acid esterification, which may underlie the 4-5-fold accumulation of free BMIPP measured in SHR muscle. Studies with isolated adipocytes and cardiomyocytes directly confirmed both the defect in FA transport and the fact that it is underestimated by BMIPP. Heart, oxidative muscle, and adipose tissue in the SHR exhibited a large increase in glucose uptake measured in vivo using [(18)F]fluorodeoxyglucose. Supplementation of the diet with short-chain fatty acids, which do not require CD36-facilitated transport, eliminated the increase in glucose uptake, the hyperinsulinemia, and the heart hypertrophy in the SHR. This indicated that lack of metabolic energy consequent to deficient FA uptake is the primary defect responsible for these abnormalities. Hypertension was not alleviated by the supplemented diet suggesting it is unrelated to fuel supply and any contribution of CD36 deficiency to this trait may be more complex to determine. It may be worth exploring whether short-chain FA supplementation can reverse some of the deleterious effects of CD36 deficiency in humans, which may include hypertrophic cardiomyopathy.
Hajri
T
T
Department of Physiology and Biophysics, State University of New York at Stony Brook, Stony Brook, New York 11794-8661, USA.
Ibrahimi
A
A
Coburn
C T
CT
Knapp
F F
FF
Kurtz
T
T
Pravenec
M
M
Abumrad
N A
NA
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D020296:Animals, Congenic; D001692:Biological Transport; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism; D006332:Cardiomegaly / Q000209:etiology* / Q000378:metabolism; D002478:Cells, Cultured; D005227:Fatty Acids / Q000378:metabolism*; D019788:Fluorodeoxyglucose F18 / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006946:Hyperinsulinism / Q000209:etiology* / Q000378:metabolism; D006973:Hypertension / Q000150:complications*; D007462:Iodobenzenes / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D014018:Tissue Distribution
D018955:CD36 Antigens; D005227:Fatty Acids; D007462:Iodobenzenes; C049338:iodofiltic acid; D019788:Fluorodeoxyglucose F18; D005947:Glucose