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 6

Them2 and PC-TP traffic saturated fatty acids into the ER and reduce fatty acyl chain unsaturation of ER membrane phospholipids in the setting of high-fat diet.

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Them2 and PC-TP traffic saturated fatty acids into the ER and reduce fat...
(A and B) Influence of Them2 (A) and PC-TP (B) on the subcellular distribution of palmitic acid (PA) and oleic acid (OA). Mouse primary hepatocytes were treated with [9,10-3H]palmitic acid (500 μM, 10 μCi/mmol) or [9,10-3H]oleic acid (500 μM, 10 μCi/mmol) for 1 hour. Radioisotope distributions to mitochondria (Mito), ER, and cytosol (Cyto) were normalized for subcellular fraction protein amounts, as well as total cellular uptake. (C–H) Four-week-old mice were fed chow or high-fat diet for 8 weeks, and livers were harvested following 6 hours of food restriction. Lipids were extracted from purified ER microsomes and subjected to mass spectrometry analysis. (C and D) Hepatic ER membrane PC (C) and PE (D) fatty acyl chain composition for Them2+/+ (n = 4) and Them2–/– (n = 4) mice. (E) Phospholipid molecular species from C and D were divided into 2 groups by fatty acyl chain saturation: ≤3 double bonds (left) or ≥4 double bonds (right). (F and G) Hepatic ER membrane PC (F) and PE (G) fatty acyl chain composition for Pctp+/+ (n = 4) and Pctp–/– (n = 4) mice. (H) Phospholipid molecular species from F and G were divided into 2 groups as in C. Error bars represent SEM. *P < 0.05 vs. WT mice. Statistical significance was determined by Student’s t test.