Lipid metabolism, oxidative stress and cell death are regulated by PKC delta in a dietary model of nonalcoholic steatohepatitis.
Steatosis, oxidative stress, and apoptosis underlie the development of nonalcoholic steatohepatitis (NASH). Protein kinase C delta (PKCδ) has been implicated in fatty liver disease and is activated in the methionine and choline-deficient (MCD) diet model of NASH, yet its pathophysiological importance towards steatohepatitis progression is uncertain. We therefore addressed the role of PKCδ in the development of steatosis, inflammation, oxidative stress, apoptosis, and fibrosis in an animal model of NASH. We fed PKCδ(-/-) mice and wildtype littermates a control or MCD diet. PKCδ(-/-) primary hepatocytes were used to evaluate the direct effects of fatty acids on hepatocyte lipid metabolism gene expression. A reduction in hepatic steatosis and triglyceride levels were observed between wildtype and PKCδ(-/-) mice fed the MCD diet. The hepatic expression of key regulators of β-oxidation and plasma triglyceride metabolism was significantly reduced in PKCδ(-/-) mice and changes in serum triglyceride were blocked in PKCδ(-/-) mice. MCD diet-induced hepatic oxidative stress and hepatocyte apoptosis were reduced in PKCδ(-/-) mice. MCD diet-induced NADPH oxidase activity and p47(phox) membrane translocation were blunted and blocked, respectively, in PKCδ(-/-) mice. Expression of pro-apoptotic genes and caspase 3 and 9 cleavage in the liver of MCD diet fed PKCδ(-/-) mice were blunted and blocked, respectively. Surprisingly, no differences in MCD diet-induced fibrosis or pro-fibrotic gene expression were observed in 8 week MCD diet fed PKCδ(-/-) mice. Our results suggest that PKCδ plays a role in key pathological features of fatty liver disease but not ultimately in fibrosis in the MCD diet model of NASH.
Boshell Diabetes and Metabolic Disease Research Program, Auburn University, Auburn, Alabama, United States of America ; College of Human Sciences, Auburn University, Auburn, Alabama, United States of America ; Bassett Research Institute, Bassett Medical Center, Bassett Healthcare Network, Cooperstown, New York, United States of America.
Michael W
MW
Greene
Bassett Research Institute, Bassett Medical Center, Bassett Healthcare Network, Cooperstown, New York, United States of America.
Christine M
CM
Burrington
Bassett Research Institute, Bassett Medical Center, Bassett Healthcare Network, Cooperstown, New York, United States of America.
Darin T
DT
Lynch
Department of Pathology, Bassett Medical Center, Bassett Healthcare Network, Cooperstown, New York, United States of America.
Samantha K
SK
Davenport
Bassett Research Institute, Bassett Medical Center, Bassett Healthcare Network, Cooperstown, New York, United States of America.
Andrew K
AK
Johnson
Bassett Research Institute, Bassett Medical Center, Bassett Healthcare Network, Cooperstown, New York, United States of America.
Melissa J
MJ
Horsman
Department of Internal Medicine, Bassett Medical Center, Bassett Healthcare Network, Cooperstown, New York, United States of America.
Saleem
S
Chowdhry
College of Human Sciences, Auburn University, Auburn, Alabama, United States of America.
Jian
J
Zhang
University of Rochester Medical Center, School of Medicine and Dentistry, Rochester, New York, United States of America.
Janet D
JD
Sparks
Department of Internal Medicine, Bassett Medical Center, Bassett Healthcare Network, Cooperstown, New York, United States of America.
Paul C
PC
Tirrell
D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000378:metabolism; D002478:Cells, Cultured; D002796:Choline Deficiency / Q000201:enzymology; D004032:Diet; D059865:Endoplasmic Reticulum Stress; D004789:Enzyme Activation; D005234:Fatty Liver / Q000201:enzymology*; D005260:Female; D015870:Gene Expression; D022781:Hepatocytes / Q000502:physiology; D050356:Lipid Metabolism; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008103:Liver Cirrhosis / Q000201:enzymology; D008297:Male; D008715:Methionine / Q000172:deficiency; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease; D018384:Oxidative Stress; D061251:Primary Cell Culture; D051745:Protein Kinase C-delta / Q000502:physiology*
D015415:Biomarkers; D008715:Methionine; C497259:Prkcd protein, mouse; D051745:Protein Kinase C-delta