Thioesterase-mediated control of cellular calcium homeostasis enables hepatic ER stress
Baran A. Ersoy, … , Ipek Alpertunga, David E. Cohen
Baran A. Ersoy, … , Ipek Alpertunga, David E. Cohen
Published November 20, 2017
Citation Information: J Clin Invest. 2018;128(1):141-156. https://doi.org/10.1172/JCI93123.
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Research Article Cell biology Metabolism

Thioesterase-mediated control of cellular calcium homeostasis enables hepatic ER stress

Abstract

The incorporation of excess saturated free fatty acids (SFAs) into membrane phospholipids within the ER promotes ER stress, insulin resistance, and hepatic gluconeogenesis. Thioesterase superfamily member 2 (Them2) is a mitochondria-associated long-chain fatty acyl-CoA thioesterase that is activated upon binding phosphatidylcholine transfer protein (PC-TP). Under fasting conditions, the Them2/PC-TP complex directs saturated fatty acyl-CoA toward β-oxidation. Here, we showed that during either chronic overnutrition or acute induction of ER stress, Them2 and PC-TP play critical roles in trafficking SFAs into the glycerolipid biosynthetic pathway to form saturated phospholipids, which ultimately reduce ER membrane fluidity. The Them2/PC-TP complex activated ER stress pathways by enhancing translocon-mediated efflux of ER calcium. The increased cytosolic calcium, in turn, led to the phosphorylation of calcium/calmodulin-dependent protein kinase II, which promoted both hepatic insulin resistance and gluconeogenesis. These findings delineate a mechanistic link between obesity and insulin resistance and establish the Them2/PC-TP complex as an attractive target for the management of hepatic steatosis and insulin resistance.

Authors

Baran A. Ersoy, Kristal M. Maner-Smith, Yingxia Li, Ipek Alpertunga, David E. Cohen

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Figure 5

Them2 and PC-TP decrease ER membrane fluidity.

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Them2 and PC-TP decrease ER membrane fluidity. (A) ER membrane fluidity ...
(A) ER membrane fluidity as measured by the excimer-to-monomer ratio of pyrenedecanoic acid (PDA). ER microsomes were purified from the livers of chow- or high-fat diet–fed Them2+/+ (n = 4) and Them2–/– (n = 4) mice following 6-hour food restriction. Error bars represent SEM. *P < 0.05 vs. Them2+/+ mice. (B) ER membrane fluidity of HEK 293E cells as a function of excimer-to-monomer ratio of PDA. Cells were treated with siRNA against Them2, PC-TP, or scrambled control, serum-starved overnight, and incubated with palmitic acid (0.5 mM) or vehicle (4.8 mM BSA) for 6 hours prior to purification of ER fractions. Error bars represent SEM for the triplicate. *P < 0.025 vs. vehicle. (C) ER membrane fluidity of mouse primary hepatocytes as determined by the inverse correlation of diphenylhexatriene (DPH) polarization anisotropy whereby decreased DPH polarization indicates increased membrane fluidity. Cells were serum-starved overnight and treated with palmitic acid (0.5 mM) (right) or vehicle (4.8 mM BSA) (left) for 6 hours. Error bars represent SEM for the triplicate. Statistical significance was determined by Student’s t test adjusted by Bonferroni correction.