Mechanisms of cell volume regulation in liver
Dr. Lidofsky is a graduate of the Medical Scientist Training Program at Columbia University, where he received the Ph.D. and M.D. degrees. Following residency training at the University of Colorado Health Sciences Center, he completed a postdoctoral fellowship in gastroenterology at the University of California San Francisco. Prior to coming to the University of Vermont, Dr. Lidofsky was Assistant Professor of Medicine and Attending Physician on the Liver Transplant Unit at the University of California San Francisco Medical Center.
The liver is subjected to major metabolic stresses that perturb cell volume. In response to swelling, dynamic reorganization of the actin cytoskeleton, in concert with the opening of volume-sensitive ion channels, allows liver cells to “breathe” to maintain physiological function. My laboratory is interested in understanding how liver cells sense changes in volume and the signaling mechanisms responsible for volume recovery. We have hypothesized that under conditions of liver cell injury, failure to achieve normal cell volume regulation potentiates hepatic necrosis. Answers to these questions will provide insight into basic mechanisms of liver physiology and are expected to identify critical cellular targets for treatment of acute and chronic liver disease.
Liver cell swelling leads to major cytoskeletal reorganization and elicits the opening of volume-sensitive potassium and chloride channels, each of which is required for volume recovery. My laboratory has shown that each of these processes is regulated by the tyrosine kinase Src. Src is activated upon hepatocellular swelling, and this leads to activation of Vav. a regulator of RhoGTPases and cytoskeletal reorganization; and to activation of phospholipase C gamma, which is required to stimulate opening of volume-sensitive potassium and chloride channels. We are now examining how Vav and other Src effectors regulate reorganization of the actin cytoskeleton after swelling and whether this process influences localization of volume-sensitive ion channels. Along these lines, preliminary studies in my laboratory suggest that the intermediate conductance potassium channel IK1 channel is the prinicpal volume-senstive potassium channel isoform in hepatocytes. We are currently studying how plasma membrane localization of IK1 is regulated in response to swelling.
Liver cell swelling evokes reversible membrane protrusions. Live imaging of calcein-loaded HTC hepatoma cells was performed under isotonic conditions (left) and following hypotonic exposure (middle 3 min, right 15 min).
Translocation of activated (pY) Src is elicited by hepatocellulat swelling. Cells were fixed at different times afetr hypotonic exposure and subsquently immunostained.
Barfod, E.T., Moore, A.L., Melnick, R.F., and Lidofsky, S.D. Src regulates distinct pathways for cell volume control through Vav and phospholipase Cgamma J Biol Chem 2005 Jul 8;280(27):25548-2557
Moore AL, Roe MW, Melnick RF, and Lidofsky SD. Calcium mobilization evoked by hepatocellular swelling is linked to activation of phospholipase Cgamma. J Biol Chem 2002 Sep 13;277(37):34030-34035
Roe MW, Moore AL, and Lidofsky SD. Purinergic-independent calcium signaling mediates recovery from hepatocellular swelling: implications for volume regulation. J Biol Chem. 2001 Aug 17;276(33):30871-3087
Barfod ET, Moore AL, and Lidofsky SD. Cloning and functional expression of a liver isoform of the small conductance Ca2+-activated K+ channel SK3. Am J Physiol Cell Physiol. 2001 Apr;280(4):C836-C842
Nietsch HH, Roe MW, Fiekers JF, Moore AL, and Lidofsky SD. Activation of potassium and chloride channels by tumor necrosis factor alpha. Role in liver cell death. J Biol Chem. 2000 Jul 7;275(27):20556-20561
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