In healthy liver tissue, insulin binding to the insulin receptor leads to recruitment of adapter insulin receptor substrate (IRS) proteins.
Lzip pgc1a series#
The actions of these hormones are mediated by a complex series of molecular signaling events downstream of their cell-surface receptors.
Conversely, following a meal, higher insulin levels stimulate hepatic glucose utilization and inhibit glucose release. High glucagon during fasting promotes glucose release from liver to provide a continuous source of fuel for peripheral tissues ( 1). These processes are controlled by the coordinated actions of the pancreatic hormones glucagon and insulin, whose ratio in circulation determines whether the liver initiates catabolic or anabolic processes to adapt to the nutritional status. It uptakes glucose, synthesizes glycogen and triglycerides following food intake, releases glucose produced by glycogenolysis or gluconeogenesis, and triggers ketogenesis during fasting. The liver plays a critical role in glucose homeostasis. These data highlight a mechanism by which PGC1A plays dual roles in the control of gluconeogenesis during the fasting-to-fed transition through regulated balance between IRS1 and IRS2 expression. We also show that increased hepatic PGC1A improves glucose homeostasis in vivo, revealing a counterregulatory role for PGC1A in repressing uncontrolled glucose production in response to insulin signaling. We illustrate that glucagon- or PGC1A-induced IRS2 expression was dependent on cAMP Response Element Binding Protein activity and that this was essential for suppression of hepatocyte gluconeogenesis in response to insulin in vitro. PGC1A drove the expression of IRS2 downstream of glucagon signaling while simultaneously reducing IRS1 expression. We found that the PGC1A level determines the relative ratio of IRS1 and IRS2 in hepatocytes, impacting insulin receptor signaling via protein kinase B/AKT (AKT). We used gain- and loss-of-function models in mouse primary hepatocytes and measured hepatocyte insulin response by gene and protein expression and ex vivo glucose production. However, how PGC1A activity impacts the hepatic insulin-signaling pathway is still unclear. In nonalcoholic fatty liver disease and in patients with type 2 diabetes, low hepatic PGC1A levels are associated with insulin resistance. The peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1A) is a fasting-induced transcriptional coactivator. The insulin-signaling pathway requires insulin receptor substrate 1 (IRS1) and IRS2, which are found to be dysregulated in diabetes and obesity.
Precise modulation of hepatic glucose metabolism is crucial during the fasting and feeding cycle and is controlled by the actions of circulating insulin and glucagon.
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