PKCδ regulates hepatic insulin sensitivity and hepatosteatosis in mice and humans.

C57BL/6J and 129S6/Sv (B6 and 129) mice differ dramatically in their susceptibility to developing diabetes in response to diet- or genetically induced insulin resistance. A major locus contributing to this difference has been mapped to a region on mouse chromosome 14 that contains the gene encoding PKCδ. Here, we found that PKCδ expression in liver was 2-fold higher in B6 versus 129 mice from birth and was further increased in B6 but not 129 mice in response to a high-fat diet. PRKCD gene expression was also elevated in obese humans and was positively correlated with fasting glucose and circulating triglycerides. Mice with global or liver-specific inactivation of the Prkcd gene displayed increased hepatic insulin signaling and reduced expression of gluconeogenic and lipogenic enzymes. This resulted in increased insulin-induced suppression of hepatic gluconeogenesis, improved glucose tolerance, and reduced hepatosteatosis with aging. Conversely, mice with liver-specific overexpression of PKCδ developed hepatic insulin resistance characterized by decreased insulin signaling, enhanced lipogenic gene expression, and hepatosteatosis. Therefore, changes in the expression and regulation of PKCδ between strains of mice and in obese humans play an important role in the genetic risk of hepatic insulin resistance, glucose intolerance, and hepatosteatosis; and thus PKCδ may be a potential target in the treatment of metabolic syndrome.

[1]  S. Sampson,et al.  Insulin stimulation of PKCδ triggers its rapid degradation via the ubiquitin-proteasome pathway. , 2010, Biochimica et biophysica acta.

[2]  S. Kasif,et al.  A Systems Biology Approach Identifies Inflammatory Abnormalities Between Mouse Strains Prior to Development of Metabolic Disease , 2010, Diabetes.

[3]  M. Uusitupa,et al.  Cholesterol absorption decreases after Roux-en-Y gastric bypass but not after gastric banding. , 2010, Metabolism: clinical and experimental.

[4]  S. Aga-Mizrachi,et al.  The regulatory domain of protein kinase C delta positively regulates insulin receptor signaling. , 2010, Journal of molecular endocrinology.

[5]  U. Smith,et al.  Protein kinase C-δ is involved in the inflammatory effect of IL-6 in mouse adipose cells , 2010, Diabetologia.

[6]  R. Garofalo,et al.  TNFalpha activation of PKCdelta, mediated by NFkappaB and ER stress, cross-talks with the insulin signaling cascade. , 2010, Cellular signalling.

[7]  Shijie Li,et al.  Bifurcation of insulin signaling pathway in rat liver: mTORC1 required for stimulation of lipogenesis, but not inhibition of gluconeogenesis , 2010, Proceedings of the National Academy of Sciences.

[8]  M. White,et al.  Irs1 serine 307 promotes insulin sensitivity in mice. , 2010, Cell metabolism.

[9]  L. Aiello,et al.  Activation of PKC-δ and SHP-1 by hyperglycemia causes vascular cell apoptosis and diabetic retinopathy , 2009, Nature Medicine.

[10]  F. Bosch,et al.  Overexpression of Kinase-Negative Protein Kinase Cδ in Pancreatic β-Cells Protects Mice From Diet-Induced Glucose Intolerance and β-Cell Dysfunction , 2009, Diabetes.

[11]  G. Cooney,et al.  Diverse roles for protein kinase C δ and protein kinase C ε in the generation of high-fat-diet-induced glucose intolerance in mice: regulation of lipogenesis by protein kinase C δ , 2009, Diabetologia.

[12]  P. Park,et al.  Thyroid hormone-related regulation of gene expression in human fatty liver. , 2009, The Journal of clinical endocrinology and metabolism.

[13]  S. Biddinger,et al.  Dissecting the role of insulin resistance in the metabolic syndrome , 2009, Current opinion in lipidology.

[14]  C. Kahn,et al.  Role of atypical protein kinase C in activation of sterol regulatory element binding protein-1c and nuclear factor kappa B (NFκB) in liver of rodents used as a model of diabetes, and relationships to hyperlipidaemia and insulin resistance , 2009, Diabetologia.

[15]  E. Eichler,et al.  Mouse segmental duplication and copy number variation , 2008, Nature Genetics.

[16]  D. Mochly‐Rosen,et al.  The PKCδ -Abl complex communicates ER stress to the mitochondria – an essential step in subsequent apoptosis , 2008, Journal of Cell Science.

[17]  J. Goldstein,et al.  Selective versus total insulin resistance: a pathogenic paradox. , 2008, Cell metabolism.

[18]  C. Kahn,et al.  Muscle-specific knockout of PKC-λ impairs glucose transport and induces metabolic and diabetic syndromes , 2007 .

[19]  G. Shulman,et al.  Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease , 2007 .

[20]  D. Cooper,et al.  Activation of the nuclear transcription factor SP-1 by insulin rapidly increases the expression of protein kinase C delta in skeletal muscle. , 2007, Cellular signalling.

[21]  Ji Luo,et al.  The p85α Regulatory Subunit of Phosphoinositide 3-Kinase Potentiates c-Jun N-Terminal Kinase-Mediated Insulin Resistance , 2007 .

[22]  K. Nakayama,et al.  Protein Kinase Cδ Plays a Non-redundant Role in Insulin Secretion in Pancreatic β Cells* , 2007, Journal of Biological Chemistry.

[23]  E. Ravussin,et al.  Inactivation of PKCtheta leads to increased susceptibility to obesity and dietary insulin resistance in mice. , 2007, American journal of physiology. Endocrinology and metabolism.

[24]  K. Nakayama,et al.  Protein kinase Cdelta plays a non-redundant role in insulin secretion in pancreatic beta cells. , 2007, The Journal of biological chemistry.

[25]  G. Shulman,et al.  Inhibition of protein kinase Cepsilon prevents hepatic insulin resistance in nonalcoholic fatty liver disease. , 2007, The Journal of clinical investigation.

[26]  C. Kahn,et al.  Muscle-specific knockout of PKC-lambda impairs glucose transport and induces metabolic and diabetic syndromes. , 2007, The Journal of clinical investigation.

[27]  E. Ravussin,et al.  Inactivation of PKCθ leads to increased susceptibility to obesity and dietary insulin resistance in mice , 2007 .

[28]  A. Bak,et al.  Protein kinase Cδ participates in insulin-induced activation of PKB via PDK1 , 2006 .

[29]  M. Quon,et al.  PKCδ-mediated IRS-1 Ser24 phosphorylation negatively regulates IRS-1 function , 2006 .

[30]  D. Cooper,et al.  Specific protein kinase C isoforms as transducers and modulators of insulin signaling. , 2006, Molecular genetics and metabolism.

[31]  C. Langefeld,et al.  Coincident Linkage of Type 2 Diabetes, Metabolic Syndrome, and Measures of Cardiovascular Disease in a Genome Scan of the Diabetes Heart Study , 2006, Diabetes.

[32]  C. Kahn,et al.  Divergent regulation of hepatic glucose and lipid metabolism by phosphoinositide 3-kinase via Akt and PKClambda/zeta. , 2006, Cell metabolism.

[33]  M. Quon,et al.  PKCdelta-mediated IRS-1 Ser24 phosphorylation negatively regulates IRS-1 function. , 2006, Biochemical and biophysical research communications.

[34]  A. Bak,et al.  Protein kinase Cdelta participates in insulin-induced activation of PKB via PDK1. , 2006, Biochemical and biophysical research communications.

[35]  F. Andreozzi,et al.  Protein Kinase C-α Regulates Insulin Action and Degradation by Interacting with Insulin Receptor Substrate-1 and 14-3-3ϵ* , 2005, Journal of Biological Chemistry.

[36]  Toshio Kuroki,et al.  PKC-delta-dependent activation of oxidative stress in adipocytes of obese and insulin-resistant mice: role for NADPH oxidase. , 2005, American journal of physiology. Endocrinology and metabolism.

[37]  C. Kahn,et al.  Genetic determinants of energy expenditure and insulin resistance in diet-induced obesity in mice. , 2004, Diabetes.

[38]  L. Glimcher,et al.  Endoplasmic Reticulum Stress Links Obesity, Insulin Action, and Type 2 Diabetes , 2004, Science.

[39]  Dan R. Littman,et al.  PKC-θ knockout mice are protected from fat-induced insulin resistance , 2004 .

[40]  Johan Auwerx,et al.  Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity , 2004, Nature.

[41]  M. Reitman,et al.  Genetic background (C57BL/6J versus FVB/N) strongly influences the severity of diabetes and insulin resistance in ob/ob mice. , 2004, Endocrinology.

[42]  Eric S. Lander,et al.  Genetic Dissection of Complex Traits with Chromosome Substitution Strains of Mice , 2004, Science.

[43]  H. Morita,et al.  Protein Kinase C (PKC) β Modulates Serine Phosphorylation of Insulin Receptor Substrate‐1 (IRS‐1)—Effect of Overexpression of PKCβ on Insulin Signal Transduction , 2004, Endocrine research.

[44]  G. Shulman,et al.  PKC-theta knockout mice are protected from fat-induced insulin resistance. , 2004, The Journal of clinical investigation.

[45]  B. Spiegelman,et al.  Muscle-specific PPARgamma-deficient mice develop increased adiposity and insulin resistance but respond to thiazolidinediones. , 2003, The Journal of clinical investigation.

[46]  H. Eldar-Finkelman,et al.  Increased glucose uptake promotes oxidative stress and PKC-delta activation in adipocytes of obese, insulin-resistant mice. , 2003, American journal of physiology. Endocrinology and metabolism.

[47]  C. Kahn,et al.  Identification of interactive loci linked to insulin and leptin in mice with genetic insulin resistance. , 2003, Diabetes.

[48]  C. Kahn,et al.  Impact of genetic background on development of hyperinsulinemia and diabetes in insulin receptor/insulin receptor substrate-1 double heterozygous mice. , 2003, Diabetes.

[49]  Bruce M. Spiegelman,et al.  Insulin-regulated hepatic gluconeogenesis through FOXO1–PGC-1α interaction , 2003, Nature.

[50]  M. Reitman,et al.  Opposite Effects of Background Genotype on Muscle and Liver Insulin Sensitivity of Lipoatrophic Mice , 2003, The Journal of Biological Chemistry.

[51]  Jerry Donovan,et al.  Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction. , 2003, Nature.

[52]  I. G. Fantus,et al.  Free fatty acid-induced hepatic insulin resistance: a potential role for protein kinase C-δ , 2002 .

[53]  M. Sajan,et al.  Knockout of PKC Enhances Insulin Signaling Through PI3K , 2002 .

[54]  M. Sajan,et al.  Knockout of PKC alpha enhances insulin signaling through PI3K. , 2002, Molecular endocrinology.

[55]  I. G. Fantus,et al.  Free fatty acid-induced hepatic insulin resistance: a potential role for protein kinase C-delta. , 2002, American journal of physiology. Endocrinology and metabolism.

[56]  E. Keeffe,et al.  Nonalcoholic fatty liver disease. , 2002, Reviews in gastroenterological disorders.

[57]  Qingbo Xu,et al.  Exacerbated vein graft arteriosclerosis in protein kinase Cδ–null mice , 2001 .

[58]  P. Formisano,et al.  The role of protein kinase C isoforms in insulin action , 2001, Journal of endocrinological investigation.

[59]  T. Kuroki,et al.  Insulin induces specific interaction between insulin receptor and protein kinase C delta in primary cultured skeletal muscle. , 2001, Molecular endocrinology.

[60]  J. Chen,et al.  Protein Kinase C-ζ Phosphorylates Insulin Receptor Substrate-1 and Impairs Its Ability to Activate Phosphatidylinositol 3-Kinase in Response to Insulin* , 2001, The Journal of Biological Chemistry.

[61]  M. Mayr,et al.  Exacerbated vein graft arteriosclerosis in protein kinase Cdelta-null mice. , 2001, The Journal of clinical investigation.

[62]  R. Hammer,et al.  Decreased IRS-2 and increased SREBP-1c lead to mixed insulin resistance and sensitivity in livers of lipodystrophic and ob/ob mice. , 2000, Molecular cell.

[63]  T. Kuroki,et al.  Protein kinase Cdelta mediates insulin-induced glucose transport in primary cultures of rat skeletal muscle. , 1999, Molecular endocrinology.

[64]  Robert V Farese,et al.  Effects of Knockout of the Protein Kinase C β Gene on Glucose Transport and Glucose Homeostasis1. , 1999, Endocrinology.

[65]  Robert V Farese,et al.  Effects of knockout of the protein kinase C beta gene on glucose transport and glucose homeostasis. , 1999, Endocrinology.

[66]  R. Pearson,et al.  Phosphorylation Sites in the Autoinhibitory Domain Participate in p70s6k Activation Loop Phosphorylation* , 1998, The Journal of Biological Chemistry.