Hepatic Activation of the FAM3C-HSF1-CaM Pathway Attenuates Hyperglycemia of Obese Diabetic Mice

Abstract

FAM3C is a member of the family with sequence similarity 3 (FAM3) gene family, and this study determined its role and mechanism in regulation of hepatic glucose/lipid metabolism. In obese diabetic mice, FAM3C expression was reduced in the liver, and hepatic FAM3C restoration improved insulin resistance, hyperglycemia, and fatty liver. FAM3C overexpression increased the expression of heat shock factor 1 (HSF1), calmodulin (CaM), and phosphorylated protein kinase B (Akt) and reduced that of gluconeogenic and lipogenic genes in diabetic mouse livers with the suppression of gluconeogenesis and lipid deposition. In cultured hepatocytes, FAM3C overexpression upregulated HSF1 expression, which elevated CaM protein level by inducing CALM1 transcription to activate Akt in a Ca- and insulin-independent manner. Furthermore, FAM3C overexpression promoted nuclear exclusion of FOXO1 and repressed gluconeogenic gene expression and gluconeogenesis in a CaM-dependent manner in hepatocytes. Hepatic HSF1 overexpression activated the CaM-Akt pathway to repress gluconeogenic and lipogenic gene expression and improve hyperglycemia and fatty liver in obese diabetic mice. In conclusion, the FAM3C-HSF1-CaM-Akt pathway plays important roles in regulating glucose and lipid metabolism in hepatocytes independent of insulin and calcium. Restoring hepatic FAM3C expression is beneficial for the management of type 2 diabetes and fatty liver.

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.…”