Hedgehog Controls Hepatic Stellate Cell Fate by Regulating Metabolism

Abstract

Background & Aims Pathogenesis of cirrhosis, a disabling outcome of defective liver repair, involves deregulated accumulation of myofibroblasts derived from quiescent hepatic stellate cells (HSC), but the mechanisms that control HSC transdifferentiation are poorly understood. We investigated whether the Hedgehog (Hh) pathway controls HSC fate by regulating metabolism. Methods Microarray, quantitative PCR, and immunoblot analyses were used to identify metabolic genes that were differentially expressed in quiescent vs myofibroblast HSC. Glycolysis and lactate production were disrupted in HSC to determine if metabolism influenced transdifferentiation. Hh signaling and hypoxia-inducible factor (HIF)1α activity were altered to identify factors that alter glycolytic activity. Changes in expression of genes that regulate glycolysis were quantified and localized in biopsy samples from patients with cirrhosis, and liver samples from mice following administration of CCl4 or bile-duct ligation. Mice were given systemic inhibitors of Hh to determine if they affect glycolytic activity of the hepatic stroma; Hh signaling was also conditionally disrupted in myofibroblasts to determine the effects of glycolytic activity. Results Transdifferentiation of cultured, quiescent HSC into myofibroblasts induced glycolysis and caused lactate accumulation. Increased expression of genes that regulate glycolysis required Hh signaling and involved induction of HIF1α. Inhibitors of Hh signaling, HIF1α, glycolysis, or lactate accumulation converted myofibroblasts to quiescent HSC. In diseased livers of animals and patients, numbers of glycolytic stromal cells were associated with the severity of fibrosis. Conditional disruption of Hh signaling in myofibroblasts reduced numbers of glycolytic myofibroblasts and liver fibrosis in mice; similar effects were observed following administration of pharmacologic inhibitors of Hh. Conclusions Hedgehog signaling controls HSC fate by regulating metabolism. These findings might be applied to diagnosis and treatment of cirrhosis.

Palmitic acid elicits hepatic stellate cell activation through inflammasomes and hedgehog signaling

“…The Hh signaling pathways has been demonstrated in HSC activation in various etiologies [9][10][11]. Gli-1 is a transcription factor and PTCH is the receptor, both of which are the downstream target genes of the Hh signaling pathway.…”

“…Enhanced activation of the Hh signaling pathway has been shown in patients with alcoholic, non-alcoholic steatohepatitis and primary biliary cholangitis [9,10], and thought to be a key factor for cross-talk between hepatocytes and HSCs during hepatic injury and fibrosis [11,12]. However, how Hh signaling modulates HSC activation in steatohepatitis is poorly understood.…”

Differentiation of progenitors in the liver: a matter of local choice

“…This observation, however, offers a tantalizing suggestion that stellate cells may have a progenitor role in the adult liver; this has been investigated by other groups in the liver (35,36) and other tissues (37). Of course stellate cells are also subject to regional signaling in the liver, and multiple developmental regulators, including Necdin-Wnt (38-40) and Hedgehog, have been implicated in the differentiation of hepatic stellate cells into fibroblasts, the latter of which control cellular metabolism to regulate fate (41). Intriguingly, differentiation of these fibroblasts is in part mediated through epigenetic regulation of PPARγ (42-44), although there is little evidence to indicate which signals might facilitate MET.…”

Dose-Dependent Metabolic Reprogramming and Differential Gene Expression in TCDD-Elicited Hepatic Fibrosis

“…Interestingly, myofibroblast activation has also been linked to a Warburg-like response wherein cells increase glycolytic flux and lactate production (Chen et al, 2012). However, few studies have examined the metabolic reprogramming underlying the development of hepatic fibrosis.…”