FAM3C activates HSF1 to suppress hepatic gluconeogenesis and attenuate hyperglycemia of type 1 diabetic mice

Abstract

FAM3C, a member of FAM3 gene family, has been shown to improve insulin resistance and hyperglycemia in obese mice. This study further determined whether FAM3C functions as a hepatokine to suppress hepatic gluconeogenesis of type 1 diabetic mice. In STZ-induced type 1 diabetic mouse liver, the FAM3C-HSF1-CaM signaling axis was repressed. Hepatic FAM3C overexpression activated HSF1-CaM-Akt pathway to repress gluconeogenic gene expression and ameliorate hyperglycemia of type 1 diabetic mice. Moreover, hepatic HSF1 overexpression also activated CaM-Akt pathway to repress gluconeogenic gene expression and improve hyperglycemia of type 1 diabetic mice. Hepatic FAM3C and HSF1 overexpression had little effect on serum insulin levels in type 1 diabetic mice. In cultured hepatocytes, conditioned medium of Ad-FAM3C-infected cells induced Akt phosphorylation. Moreover, Akt activation and gluconeogenesis repression induced by FAM3C overexpression were reversed by the treatment with anti-FAM3C antibodies. Treatment with recombinant FAM3C protein induced Akt activation in a HSF1- and CaM-dependent manner in cultured hepatocytes. Furthermore, recombinant FAM3C protein repressed gluconeogenic gene expression and gluconeogenesis by inactivating FOXO1 in a HSF1-dependent manner in cultured hepatocytes. In conclusion, FAM3C is a new hepatokine that suppresses hepatic gluconeogenic gene expression and gluconeogenesis independent of insulin by activating HSF1-CaM-Akt pathway.

FAM3C‐YY1 axis is essential for TGFβ‐promoted proliferation and migration of human breast cancer MDA‐MB‐231 cells via the activation of HSF1

“…However, whether they are coordinated to promote the development of cancers remains unknown. 44 The current and our previous findings 27,28 revealed that FAM3C likely mediates TGFβ-promoted Akt activation in the pathogenesis of EMT through YY1-HSF1 signalling axis. FAM3C up-regulates YY1 to induce HSF1 expression, finally activating Akt-Cyclin D1 pathway to promote the proliferation and migration of breast cancer cells.…”

“…27,28 However, in case of TGFβ overproduction, long-term activation of FAM3C-YY1-HSF1 pathway will trigger the development of cancers in various tissues including breast tissue by promoting excessive Akt activation. Under insulin resistance, repression of FAM3C by the factors such as fatty acids will impair YY1-HSF1-Akt pathway to enhance hepatic gluconeogenesis and lipogenesis, exaggerating hyperglycaemia and fatty liver.…”

“…27,28 All primer sequences for real-time PCR assays were listed in Table S2. The protocol for real-time PCR analysis is as following: 95°C for 5 minutes, followed by 40 cycles at 95°C for 30 seconds, 59°C for 30 seconds and 72°C for 30 seconds.…”

“…We had recently demonstrated that FAM3C activates HSF1 to induce calmodulin 1 (CALM1) gene transcription, elevating calmodulin (CaM) protein level to activate Akt pathway and repress gluconeogenesis and lipogenesis independent of insulin and calcium in hepatocytes 27,28. However, how FAM3C activates HSF1 transcription remains unrevealed in hepatocytes in our previous studies 27,28. Collectively, these previous findings had raised an important hypothesis that FAM3C may activate HSF1-Akt pathway to promote breast cancer growth.This study aimed to determine whether and how FAM3C activated HSF1 transcription to promote the proliferation and migration of breast cancer cells.…”

“…It has been established that FAM3A, FAM3B and FAM3C of FAM3 gene family are important modulators of Akt activity via different pathways in hepatocytes 26. We had recently demonstrated that FAM3C activates HSF1 to induce calmodulin 1 (CALM1) gene transcription, elevating calmodulin (CaM) protein level to activate Akt pathway and repress gluconeogenesis and lipogenesis independent of insulin and calcium in hepatocytes 27,28. However, how FAM3C activates HSF1 transcription remains unrevealed in hepatocytes in our previous studies 27,28.…”