Abstract
As a common sequel to obesity, plasma and intracellular free fatty acid (FFA) concentrations are elevated and, as a consequence, manifold disturbances in metabolism may ensue. Biochemical processes in the cytosol and organelles, such as mitochondria and endoplasmic reticulum (ER), can be disturbed. In the ER, the maintenance of a high calcium gradient is indispensable for viability. In sarcoplasmic reticulum, selective FFA can induce ER stress by disrupting luminal calcium homeostasis; however, there are limited studies in hepatic microsomes. Our studies found that FFA has a noxious effect on rat hepatic microsomal calcium flux, and the extent of which depended on the number of double bonds and charge. Furthermore, insofar as the FFA had no effect on microsomal calcium efflux, their inhibitory action primarily involves calcium influx. Finally, other cationic channels have been found in hepatic ER, and evidence is presented of their interaction with the Ca2+ ATPase pump.
Highlights
One function of the endoplasmic reticulum (ER) is to properly assemble proteins that are eventually destined for intracellular organelles, cytoplasm, or the cell surface [1]
The more double bonds present, the greater the inhibition. This finding is in concert with previous study in sarcoplasmic reticulum microsomes, namely, that unsaturated fatty acids are stronger inhibitors of ER calcium uptake than saturated fatty acids [20]
To wit, unsaturated free fatty acid (FFA) can increase the calcium affinity constant for albumin binding compared with saturated FFA, the maximum Ca+2 binding only increases by 20%
Summary
One function of the endoplasmic reticulum (ER) is to properly assemble proteins that are eventually destined for intracellular organelles, cytoplasm, or the cell surface [1]. The ER is the primary calcium reservoir [2] and, as such, governs the activity of multiple enzymes and chaperones involved in protein folding and ER function. To accomplish these tasks, high Ca2+ levels in the ER are a requisite [3]. In the ER, there is a thousand-fold calcium gradient over the cytosol [2,4]. Sarcoplasmic reticulum Ca2+-ATPase (SERCA) is a Ca2+-transporter ATPase, the function of which is the uptake of Ca2+ from cytosol into the ER lumen. SERCA2b expression was 50% reduced in high-fat diet fed mice vs normal fat diet fed mice. SERCA2b overexpression reduces liver triglyceride level by 25%, reduces lipogenic gene expression levels, and free fatty acid (FFA) synthase by 73% [3]
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