Signalling mechanisms linking hepatic glucose and lipid metabolism

Abstract

Fatty liver and hepatic triglyceride accumulation are strongly associated with obesity, insulin resistance and type 2 diabetes, and are subject to nutritional influences. Hepatic regulation of glucose and lipid homeostasis is influenced by a complex system of hormones, hormonally regulated signalling pathways and transcription factors. Recently, considerable progress has been made in elucidating molecular pathways and potential factors that are affected in insulin-resistant states. In this review we discuss some of the key factors that are involved in both the regulation of glucose and lipid metabolism in the liver. Understanding the molecular network that links hepatic lipid accumulation and impaired glucose metabolism may provide targets for dietary or pharmacological interventions.

Subtle metabolic and liver gene transcriptional changes underlie diet-induced fatty liver susceptibility in insulin-resistant mice

“…The definition of coordinated changes in plasma metabolites and gene expression could help test causal relationships between insulin resistance and NAFLD. Hepatic insulin-and glucose-responsive metabolic systems play a central role in the regulation of carbohydrate and lipid metabolism [22]. Interpretation of gene expression profiling data relies on mechanistic models integrating molecular markers of disease onset and progression, which derive from clinical and experimental observations.…”

“…SREBF1c is a transcription factor involved in carbohydrate and lipid metabolism [8]. Its activation, which simulates lipogenic enzymes in the liver, is mediated by increased glucose and insulin concentrations [22,26]. In fat-fed 129S6 mice, hyperglycaemia and hyperinsulinaemia could directly result in the upregulation of Srebf1c transcription, which can in turn enhance the transcription of Abca1, encoding an Apo-A1 binding protein controlling cholesterol efflux [27].…”

PGC-1α, glucose metabolism and type 2 diabetes mellitus

“…Thus, AMPK is now recognized as a promising drug target for the treatment of T2DM. There is a strong correlation between AMPK/PGC-1α signaling pathway and T2DM (Weickert & Pfeiffer 2006). For instance, metformin, one of the most widely prescribed drugs for T2DM, exerts a strong antihyperglycemic effect partly though the increasing of PGC-1α expression, via its upstream kinase AMPK (Aatsinki et al 2014).…”

Hepatitis C virus infection and insulin resistance

“…Both insulin resistance and diabetes can adversely affect the course of chronic hepatitis C (CHC), leading to enhanced steatohepatitis and liver fibrosis [30][31][32] . Insulin resistance, associated with type 2 diabetes, can promote fatty liver, and excessive hepatic accumulation of fat may promote insulin resistance and therefore contribute to the pathogenesis of the metabolic syndrome [33] . Insulin resistance is a critical component of type 2 diabetes mellitus pathogenesis.…”