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 January 2, 2018; First published November 20, 2017
Citation Information: J Clin Invest. 2018;128(1):141-156. https://doi.org/10.1172/JCI93123.
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Categories: 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 1

Them2 and PC-TP regulate ER stress in mice.

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Them2 and PC-TP regulate ER stress in mice. (A) The livers of Them2–/– a...
(A) The livers of Them2–/– and Pctp–/– mice are protected against ER stress due to high-fat feeding. Liver homogenates from high-fat-fed Them2+/+ (n = 8), Them2–/– (n = 9), Pctp+/+ (n = 5), and Pctp–/– (n = 5) mice were subjected to immunoblot analyses, and bands were quantified by densitometry and normalized to β-actin. Error bars represent SEM. *P < 0.05 compared with Them2–/– or Pctp+/+, ‡P = 0.057 compared with Pctp+/+. (B and C) Them2 and PC-TP modulate the resolution of hepatic ER stress following refeeding. Liver homogenates (n = 3 per genotype) were subjected to immunoblot analyses, and bands were quantified by densitometry. (D) The influence of refeeding on the interactions between PC-TP and Them2 was determined by coimmunoprecipitation in the liver lysates that were harvested from Pctp+/+ (n = 3) mice, and bands were quantified by densitometry. (E–N) Them2 or PC-TP expression enables tunicamycin-induced liver injury. Eight-week-old chow-fed mice were injected i.p. with tunicamycin (0.25 mg/kg body weight) or vehicle (DMSO, 0.25% v/v) for 2 consecutive days. (E and F) Body weights (n = 3 per genotype) following tunicamycin injections (arrows). (G) Livers were harvested and imaged 6 hours following food restriction. Liver sections were subjected to hematoxylin and eosin (H&E) staining. Microscope images (×60) are representatives of n = 3. (H–M) Livers were analyzed for the concentrations of triglycerides (TG) (H and K), NEFA (I and L), and total cholesterol (J and M). (N) ER stress markers were detected in the liver lysates by immunoblot analyses. Error bars represent SEM. *P < 0.05 compared with WT. Statistical significance was determined by Student’s t test.