Thioesterase-mediated control of cellular calcium homeostasis enables hepatic ER stress
Baran A. Ersoy, Kristal M. Maner-Smith, Yingxia Li, Ipek Alpertunga, David E. Cohen
Baran A. Ersoy, Kristal M. Maner-Smith, Yingxia Li, Ipek Alpertunga, David E. Cohen
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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 2

Them2–/– and Pctp–/– mouse primary hepatocytes are protected against induction of ER stress by tunicamycin and palmitic acid.

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Them2–/– and Pctp–/– mouse primary hepatocytes are protected against in...
(A and B) ER stress was induced in mouse primary hepatocytes that were harvested from Them2+/+ and Them2–/– mice (A) and Pctp+/+ and Pctp–/– mice (B) by treatment of cells with tunicamycin (1 μg/ml) for 5 hours. (C and D) ER stress was induced in mouse primary hepatocytes harvested from Them2+/+ and Them2–/– mice (C) and Pctp+/+ and Pctp–/– mice (D) by treatment of cells with palmitic acid (0.5 mM) or vehicle (4.8 mM BSA) for 6 hours. Rescue of SFA-induced ER stress was performed by treatment of cells with the monounsaturated NEFA oleic acid (0.5 mM) in the presence of palmitic acid (0.5 mM) or vehicle (4.8 mM BSA) for 6 hours. Hepatocytes were serum-starved overnight before treatments. Immunoblots are representative of 3 independent experiments.