Canonical and non-canonical Hedgehog signalling and the control of metabolism

Abstract

Obesity and diabetes represent key healthcare challenges of our day, affecting upwards of one billion people worldwide. These individuals are at higher risk for cancer, stroke, blindness, heart and cardiovascular disease, and to date, have no effective long-term treatment options available. Recent and accumulating evidence has implicated the developmental morphogen Hedgehog and its downstream signalling in metabolic control. Generally thought to be quiescent in adults, Hedgehog is associated with several human cancers, and as such, has already emerged as a therapeutic target in oncology. Here, we attempt to give a comprehensive overview of the key signalling events associated with both canonical and non-canonical Hedgehog signalling, and highlight the increasingly complex regulatory modalities that appear to link Hedgehog and control metabolism. We highlight these key findings and discuss their impact for therapeutic development, cancer and metabolic disease.

Glucose Induces Sensitivity to Oxygen Deprivation and Modulates Insulin/IGF-1 Signaling and Lipid Biosynthesis inCaenorhabditis elegans

“…It is possible that in the daf-2(e1370) mutant the lipid profile is altered in such a way that is conducive for maintenance of cellular structures and function during anoxia stress (Castro et al 2013) and that knockdown of genes involved with lipid biosynthesis would disrupt lipid homeostasis. It has recently been shown that ceramides are involved with a surveillance system that detects mitochondrial defects (Liu et al 2014); thus, it is possible that the (Puri et al 2013;Teperino et al 2014) clec-70 CRD-4 (28) C-type carbohydrate recognition domain C-type lectin; binds sugar; implicated in innate immunity response (Hitchen et al 1998;Feinberg et al 2000) col-60 COL6A3 (46) Collagen Collagen; deposition in obesity patients (McCulloch et al 2014) daf-2(e1370) animal requires specific ceramides to defend against the toxic effects a glucose-supplemented diet has on the mitochondria. It remains to be determined if the sod-2/3 antioxidant system will function independently or in conjunction with ceramide and fatty acid molecules in promoting glucose-fed anoxia survival in the daf-2(e1370) animal.…”

Increment of HFABP Level in Coronary Artery In-Stent Restenosis Segments in Diabetic and Nondiabetic Minipigs: HFABP Overexpression Promotes Multiple Pathway-Related Inflammation, Growth and Migration in Human Vascular Smooth Muscle Cells

“…Induction of these pathways is also verified in ISR versus non-ISR tissue. Substantial evidence indicates that the Wnt, HH, BMP and Notch pathways play a role in the physiological differentiation and homeostasis of epithelial cells, and that the alterations of these pathways contributes to the pathophysiology of skeletal and cardiovascular diseases and tumorigenesis [17,18,19,20,21,22,23,24]. These pathways also appear to have cross-talk among them [25,26,27,28,29,30,31].…”

Sonic hedgehog signaling in kidney fibrosis: a master communicator

“…It is increasingly recognized that not all Shh signaling proceeds through Gli protein activation, thanks to the studies in the fields of cancer biology, neurological disorders and metabolic diseases (Aberger et al, 2012; Jenkins, 2009; Teperino et al, 2014; Zhao et al, 2010). The definition of “non-canonical Shh signaling” refers to the cellular responses to Shh ligand that are independent of the activation of the Gli family of transcription factors.…”