The Coactivator SRC-1 Is an Essential Coordinator of Hepatic Glucose Production

Abstract

Gluconeogenesis makes a major contribution to hepatic glucose production, a process critical for survival in mammals. In this study, we identify the p160 family member, SRC-1, as a key coordinator of the hepatic gluconeogenic program in vivo. SRC-1 null mice displayed hypoglycemia secondary to a deficit in hepatic glucose production. Selective re-expression of SRC-1 in the liver restored blood glucose levels to a normal range. SRC-1 was found induced upon fasting to coordinate in a cell-autonomous manner, the gene expression of rate-limiting enzymes of the gluconeogenic pathway. At the molecular level, the main role of SRC-1 was to modulate the expression and the activity of C/EBPα through a feed-forward loop in which SRC-1 used C/EBPα to transactivate pyruvate carboxylase, a crucial gene for initiation of the gluconeogenic program. We propose that SRC-1, acts as a novel and critical mediator of glucose homeostasis in the liver by adjusting the transcriptional activity of key genes involved in the hepatic glucose production machinery.

Targeting steroid receptor coactivator 1 with antisense oligonucleotides increases insulin-stimulated skeletal muscle glucose uptake in chow-fed and high-fat-fed male rats

“…Our finding that SRC1 knockdown in the liver does not affect gluconeogenesis is contrary to previous studies of SRC1 Ϫ/Ϫ mice (23). There are several possibilities that may explain these discrepancies.…”

“…SRC1 Ϫ/Ϫ mice have impairment in brown adipose tissue (BAT) function that makes them prone to weight gain potentially through decreased activation of PGC-1␣, although this phenotype is not always apparent (30). And recently, studies investigating the mechanism of fasting hypoglycemia in SRC1 Ϫ/Ϫ mice suggest that SRC1 regulates hepatic gluconeogenic gene expression in the fed and fasted states (23).…”

“…Additionally, studies using the SRC1 global knockout mice have shown that SRC1 is required for uterine growth and function, prostate development, mammary gland growth and elongation, brain development and function, and metabolism (20,23,24,28,31,49,50,52). SRC1 Ϫ/Ϫ mice also have features of thyroid hormone resistance, with evidence that SRC1 is critical for proper activation of the thyroid hormone receptor-␤ (48).…”

Role of co-regulators in metabolic and transcriptional actions of thyroid hormone

“…At the same time, lack of SRC1 also leads to hypoglycemia in fed and fasting states, at least partly due to impaired hepatic gluconeogenesis, as SRC1 is involved in activation of transcription of key : gluconeogenic enzymes by CCAAT/enhancer-binding protein (CEBPA) (Louet et al 2010). It has also been reported that Src1 is important for normal amino acid metabolism in the liver (Tannour-Louet et al 2014).…”

Steroid Receptor Coactivators and Their Expression, Regulation and Functional Role in Endocrine Responsive and Resistant Breast Cancer

“…The gene is located on the short arm of chromosome 2 at position 2p23 (Carapeti et al, 1998). SRC-1 -/-mice show partial steroid hormone resistance and hepatic insufficiency (Xu et al, 1998;Louet et al, 2010). Noteworthy, ovariectomized female SRC-1 -/-mice have decreased uterine growth and reduced mammary gland ductal side branching and alveolar formation in response to estrogen compared with wild-type mice, indicating a role of SRC-1 in estrogen-regulated breast development (Xu et al, 1998;Xu & Li, 2003).…”