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 7

Them2 and PC-TP regulate the activity of CaMKII.

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Them2 and PC-TP regulate the activity of CaMKII. (A and B) Influence of ...
(A and B) Influence of Them2 or PC-TP knockdown on CaMKII activation was determined in HEK 293E cells treated with Bapta-AM (5 nM) (A), anisomycin (200 μM) (B), or vehicle for 1 hour. Immunoblots represent 3 independent experiments. (C) Reduced activation of CaMKII in livers of Them2–/– mice. Liver homogenates from 12-week-old high-fat diet–fed Them2+/+ (n = 4) and Them2–/– (n = 5) mice were subjected to immunoblot analyses, and bands were quantified by densitometry and normalized to β-actin as control. Error bars represent SEM. *P < 0.05 vs. Them2+/+. Statistical significance was determined by Student’s t test. (D) Postulated mechanism by which Them2 and PC-TP regulate hepatic glucose homeostasis. In the setting of overnutrition, Them2 and PC-TP are proposed to facilitate the incorporation of SFAs into the ER membrane phospholipid composition, which induces loss of ER calcium into the cytosol via translocons. Increased cytosolic calcium accumulation activates CaMKII, which in turn promotes insulin resistance and enhances hepatic glucose production. Efflux of ER calcium promotes ER stress, which is associated with insulin resistance and de novo lipogenesis.