Date Published: December 11, 2018
Publisher: Public Library of Science
Author(s): Tsunehisa Yamamoto, Jin Endo, Masaharu Kataoka, Tomohiro Matsuhashi, Yoshinori Katsumata, Kohsuke Shirakawa, Naohiro Yoshida, Sarasa Isobe, Hidenori Moriyama, Shinichi Goto, Kaoru Yamashita, Hiroki Nakanishi, Yuta Shimanaka, Nozomu Kono, Ken Shinmura, Hiroyuki Arai, Keiichi Fukuda, Motoaki Sano, Tohru Minamino.
Increase in saturated fatty acid (SFA) content in membrane phospholipids dramatically affects membrane properties and cellular functioning. We sought to determine whether exogenous SFA from the diet directly affects the degree of membrane phospholipid unsaturation in adult hearts and if these changes correlate with contractile dysfunction. Although both SFA-rich high fat diets (HFDs) and monounsaturated FA (MUFA)-rich HFDs cause the same degree of activation of myocardial FA uptake, triglyceride turnover, and mitochondrial FA oxidation and accumulation of toxic lipid intermediates, the former induced more severe diastolic dysfunction than the latter, which was accompanied with a decrease in membrane phospholipid unsaturation, induction of unfolded protein response (UPR), and a decrease in the expression of Sirt1 and stearoyl-CoA desaturase-1 (SCD1), catalyzing the conversion of SFA to MUFA. When the SFA supply in the heart overwhelms the cellular capacity to use it for energy, excess exogenous SFA channels to membrane phospholipids, leading to UPR induction, and development of diastolic dysfunction.
Accumulation of excess lipids in non-adipose tissues, due to overeating or a sedentary lifestyle, leads to cell dysfunction or death. This phenomenon, known as lipotoxicity, plays an important role in the pathogenesis of heart failure in humans [1–4].
The adult cardiomyocytes in actively contracting and load-bearing myocardium exhibit the high ATP demand of cells with high FA oxidation rates and capacity, with high FAO enzyme expression and mitochondrial density. It seems unlikely that such adult cardiomyocytes in situ would channel a substantial amount of exogenous FA toward lipid membranes, unlike other cell types that have no incentive to burn fat. In this study, we found that when FA overload in the heart overwhelms the cellular capacity to use it for energy, the surplus of FA is channeled into membrane phospholipids. In such situations, the FA composition of membrane phospholipids in adult cardiomyocytes is directly affected by exogenous FA from the diet.