RNAi screening in primary human hepatocytes of genes implicated in genome-wide association studies for roles in type 2 diabetes identifies roles for CAMK1D and CDKAL1, among others, in hepatic glucose regulation.
Genome-wide association (GWA) studies have described a large number of new candidate genes that contribute to of Type 2 Diabetes (T2D). In some cases, small clusters of genes are implicated, rather than a single gene, and in all cases, the genetic contribution is not defined through the effects on a...
Guardado en:
| Autores principales: | , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Public Library of Science (PLoS)
2013
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/18b259ba506c499785a9716e224b0b31 |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:18b259ba506c499785a9716e224b0b31 |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:18b259ba506c499785a9716e224b0b312021-11-18T07:40:53ZRNAi screening in primary human hepatocytes of genes implicated in genome-wide association studies for roles in type 2 diabetes identifies roles for CAMK1D and CDKAL1, among others, in hepatic glucose regulation.1932-620310.1371/journal.pone.0064946https://doaj.org/article/18b259ba506c499785a9716e224b0b312013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23840313/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Genome-wide association (GWA) studies have described a large number of new candidate genes that contribute to of Type 2 Diabetes (T2D). In some cases, small clusters of genes are implicated, rather than a single gene, and in all cases, the genetic contribution is not defined through the effects on a specific organ, such as the pancreas or liver. There is a significant need to develop and use human cell-based models to examine the effects these genes may have on glucose regulation. We describe the development of a primary human hepatocyte model that adjusts glucose disposition according to hormonal signals. This model was used to determine whether candidate genes identified in GWA studies regulate hepatic glucose disposition through siRNAs corresponding to the list of identified genes. We find that several genes affect the storage of glucose as glycogen (glycolytic response) and/or affect the utilization of pyruvate, the critical step in gluconeogenesis. Of the genes that affect both of these processes, CAMK1D, TSPAN8 and KIF11 affect the localization of a mediator of both gluconeogenesis and glycolysis regulation, CRTC2, to the nucleus in response to glucagon. In addition, the gene CDKAL1 was observed to affect glycogen storage, and molecular experiments using mutant forms of CDK5, a putative target of CDKAL1, in HepG2 cells show that this is mediated by coordinate regulation of CDK5 and PKA on MEK, which ultimately regulates the phosphorylation of ribosomal protein S6, a critical step in the insulin signaling pathway.Steven HaneyJuan ZhaoShiwani TiwariKurt EngLin T GueyEric TienPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 6, p e64946 (2013) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Medicine R Science Q |
| spellingShingle |
Medicine R Science Q Steven Haney Juan Zhao Shiwani Tiwari Kurt Eng Lin T Guey Eric Tien RNAi screening in primary human hepatocytes of genes implicated in genome-wide association studies for roles in type 2 diabetes identifies roles for CAMK1D and CDKAL1, among others, in hepatic glucose regulation. |
| description |
Genome-wide association (GWA) studies have described a large number of new candidate genes that contribute to of Type 2 Diabetes (T2D). In some cases, small clusters of genes are implicated, rather than a single gene, and in all cases, the genetic contribution is not defined through the effects on a specific organ, such as the pancreas or liver. There is a significant need to develop and use human cell-based models to examine the effects these genes may have on glucose regulation. We describe the development of a primary human hepatocyte model that adjusts glucose disposition according to hormonal signals. This model was used to determine whether candidate genes identified in GWA studies regulate hepatic glucose disposition through siRNAs corresponding to the list of identified genes. We find that several genes affect the storage of glucose as glycogen (glycolytic response) and/or affect the utilization of pyruvate, the critical step in gluconeogenesis. Of the genes that affect both of these processes, CAMK1D, TSPAN8 and KIF11 affect the localization of a mediator of both gluconeogenesis and glycolysis regulation, CRTC2, to the nucleus in response to glucagon. In addition, the gene CDKAL1 was observed to affect glycogen storage, and molecular experiments using mutant forms of CDK5, a putative target of CDKAL1, in HepG2 cells show that this is mediated by coordinate regulation of CDK5 and PKA on MEK, which ultimately regulates the phosphorylation of ribosomal protein S6, a critical step in the insulin signaling pathway. |
| format |
article |
| author |
Steven Haney Juan Zhao Shiwani Tiwari Kurt Eng Lin T Guey Eric Tien |
| author_facet |
Steven Haney Juan Zhao Shiwani Tiwari Kurt Eng Lin T Guey Eric Tien |
| author_sort |
Steven Haney |
| title |
RNAi screening in primary human hepatocytes of genes implicated in genome-wide association studies for roles in type 2 diabetes identifies roles for CAMK1D and CDKAL1, among others, in hepatic glucose regulation. |
| title_short |
RNAi screening in primary human hepatocytes of genes implicated in genome-wide association studies for roles in type 2 diabetes identifies roles for CAMK1D and CDKAL1, among others, in hepatic glucose regulation. |
| title_full |
RNAi screening in primary human hepatocytes of genes implicated in genome-wide association studies for roles in type 2 diabetes identifies roles for CAMK1D and CDKAL1, among others, in hepatic glucose regulation. |
| title_fullStr |
RNAi screening in primary human hepatocytes of genes implicated in genome-wide association studies for roles in type 2 diabetes identifies roles for CAMK1D and CDKAL1, among others, in hepatic glucose regulation. |
| title_full_unstemmed |
RNAi screening in primary human hepatocytes of genes implicated in genome-wide association studies for roles in type 2 diabetes identifies roles for CAMK1D and CDKAL1, among others, in hepatic glucose regulation. |
| title_sort |
rnai screening in primary human hepatocytes of genes implicated in genome-wide association studies for roles in type 2 diabetes identifies roles for camk1d and cdkal1, among others, in hepatic glucose regulation. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2013 |
| url |
https://doaj.org/article/18b259ba506c499785a9716e224b0b31 |
| work_keys_str_mv |
AT stevenhaney rnaiscreeninginprimaryhumanhepatocytesofgenesimplicatedingenomewideassociationstudiesforrolesintype2diabetesidentifiesrolesforcamk1dandcdkal1amongothersinhepaticglucoseregulation AT juanzhao rnaiscreeninginprimaryhumanhepatocytesofgenesimplicatedingenomewideassociationstudiesforrolesintype2diabetesidentifiesrolesforcamk1dandcdkal1amongothersinhepaticglucoseregulation AT shiwanitiwari rnaiscreeninginprimaryhumanhepatocytesofgenesimplicatedingenomewideassociationstudiesforrolesintype2diabetesidentifiesrolesforcamk1dandcdkal1amongothersinhepaticglucoseregulation AT kurteng rnaiscreeninginprimaryhumanhepatocytesofgenesimplicatedingenomewideassociationstudiesforrolesintype2diabetesidentifiesrolesforcamk1dandcdkal1amongothersinhepaticglucoseregulation AT lintguey rnaiscreeninginprimaryhumanhepatocytesofgenesimplicatedingenomewideassociationstudiesforrolesintype2diabetesidentifiesrolesforcamk1dandcdkal1amongothersinhepaticglucoseregulation AT erictien rnaiscreeninginprimaryhumanhepatocytesofgenesimplicatedingenomewideassociationstudiesforrolesintype2diabetesidentifiesrolesforcamk1dandcdkal1amongothersinhepaticglucoseregulation |
| _version_ |
1718423080672428032 |