Hedgehog signaling is a potent regulator of liver lipid metabolism and reveals a GLI-code associated with steatosis

Matz‐Soja, Madlen; Rennert, Christiane; Schönefeld, Kristin; Aleithe, Susanne; Boettger, Jan; Schmidt‐Heck, Wolfgang; Weiss, Thomas S.; Hovhannisyan, Amalya; Zellmer, Sebastian; Klöting, Nora; Schulz, Angela; Kratzsch, Jürgen; Guthke, R; Gebhardt, Rolf

doi:10.7554/elife.13308

Cited by 64 publications

(76 citation statements)

References 73 publications

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“…This is in agreement with our observation in HPE patients— most of whom are not overweight—and suggests a new mechanism of NAFLD manifestation. These findings are in concert with the recent work of Matz-Soja et al [12] showing that conditional hepatocyte-specific deletion of Smoothened (a Patched-inhibited Hh co-receptor) in adult mice produces liver steatosis independent of insulin resistance. Previous studies have indicated that Hh signaling defects stimulate systemic adipogenesis [11, 34, 35], which can lead to metabolic complications such as dyslipidemia, type 2 diabetes and NAFLD.…”

Section: Discussionsupporting

confidence: 86%

“…Some studies have proposed that increased PPARγ expression promotes liver steatosis and have attributed a causal role to PPARγ through mechanisms involving activation of lipogenic genes and de novo lipogenesis [12, 31]. Furthermore, it has been demonstrated that PPARγ inhibits monocyte and macrophage inflammatory responses and prevents myofibroblastic transdifferentiation of HSC [31], which explains the reduced expression or lack of induction of fibrosis markers and pro-inflammatory cytokines.…”

Section: Discussionmentioning

confidence: 99%

“…Beyond embryogenesis, several types of cells that reside in healthy adult livers are capable of producing and/or responding to Hh ligands and this pathway is activated in many types of acute and chronic liver injury, with tissue responses including expansion of liver progenitor populations, myofibroblast accumulation and fibrogenesis, repair-associated inflammation, and vascular remodeling [9]. In addition to its role in liver repair, several studies have also suggested Hh signaling involvement in the regulation of lipid metabolism in adipocytes [10, 11] and more recently, in hepatocytes [12], This cumulative evidence suggests an important role for Hh signaling in liver function, but the effect of human germline Hh signaling mutations on the development and progression of NAFLD has not been investigated.…”

Section: Introductionmentioning

confidence: 99%

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Human germline hedgehog pathway mutations predispose to fatty liver

Guillen-Sacoto

Martinez

Abe

et al. 2017

Journal of Hepatology

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Background & Aims Non-alcoholic fatty liver disease (NAFLD) is the most common form of liver disease. Activation of hedgehog (Hh) signaling has been implicated in the progression of NAFLD and proposed as a therapeutic target; however, the effects of Hh signaling inhibition have not been studied in humans with germline mutations affecting this pathway. Methods Patients with holoprosencephaly (HPE), a disorder associated with germline mutations disrupting Sonic hedgehog (SHH) signaling, were clinically evaluated for NAFLD. A combined mouse model of Hh signaling attenuation (Gli2 heterozygous null: Gli2+/−) and diet-induced NAFLD was used to examine aspects of NAFLD and hepatic gene expression profiles, including molecular markers of hepatic fibrosis and inflammation. Results Patients with HPE had a higher prevalence of liver steatosis compared to the general population, independent of obesity. Exposure of Gli2+/− mice to fatty liver-inducing diets resulted in increased liver steatosis compared to wild-type mice. Similar to humans, this effect was independent of obesity in the mutant mice and was associated with decreased expression of pro-fibrotic and pro-inflammatory genes, and increased expression of PPARγ, a potent anti-fibrogenic and anti-inflammatory regulator. Interestingly, tumor suppressors p53 and p16INK4 were found to be downregulated in the Gli2+/− mice exposed to high-fat diet. Conclusions Our results indicate that germline mutations disrupting Hh signaling promote liver steatosis, independent of obesity, with reduced fibrosis. While Hh signaling inhibition has been associated with a better NAFLD prognosis, further studies are required to evaluate the long-term effects of mutations affecting this pathway.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Human germline hedgehog pathway mutations predispose to fatty liver

Guillen-Sacoto

Martinez

Abe

et al. 2017

Journal of Hepatology

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“…Mouse liver displayed a perivenous zonation of IHh [164] and conditional hepatocyte-specific deletion of SMO resulted in periportal lipid accumulation and up-regulation of key lipogenic transcription factors such as SREBP and PPARs and enzymes such as FASN [165]. The latter displayed a reversed zonation in the SMO deleted mice; instead of being perivenous [8], [166] like in the control mice, FASN was detected in the periportal zone of the SMO knockouts.…”

Section: Hedgehog Signalingmentioning

confidence: 96%

Metabolic zonation of the liver: The oxygen gradient revisited

2017

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The liver has a multitude of functions which are necessary to maintain whole body homeostasis. This requires that various metabolic pathways can run in parallel in the most efficient manner and that futile cycles are kept to a minimum. To a large extent this is achieved due to a functional specialization of the liver parenchyma known as metabolic zonation which is often lost in liver diseases. Although this phenomenon is known for about 40 years, the underlying regulatory pathways are not yet fully elucidated. The physiologically occurring oxygen gradient was considered to be crucial for the appearance of zonation; however, a number of reports during the last decade indicating that β-catenin signaling, and the hedgehog (Hh) pathway contribute to metabolic zonation may have shifted this view. In the current review we connect these new observations with the concept that the oxygen gradient within the liver acinus is a regulator of zonation. This is underlined by a number of facts showing that the β-catenin and the Hh pathway can be modulated by the hypoxia signaling system and the hypoxia-inducible transcription factors (HIFs). Altogether, we provide a view by which the dynamic interplay between all these pathways can drive liver zonation and thus contribute to its physiological function.

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“…The steatogenic effect of Gli suppression resulted from a skewing of lipid metabolism towards lipogenesis through the induction of lipogenic factors such as sterol regulatory element-binding protein (SREBP)-1c and adiponutrin/patatin-like phospholipase domain-containing protein-3 (PNPLA-3). Furthermore, activation of the Hh pathway (through SUFU knockdown, small molecule Shh agonists or Gli overexpression) reversed the steatogenic phenotype in hepatocytes derived from genetic models of obesity-related NAFLD, i.e., ob/ob mice and melanocortin-4 knockout mice (Matz-Soja et al, 2016). …”

Section: Hedgehog Pathway In Nonalcoholic Fatty Liver Diseasementioning

confidence: 99%

The hedgehog pathway in nonalcoholic fatty liver disease

Machado

Diehl

2018

Critical Reviews in Biochemistry and Molecular Biology

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Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of obesity-associated liver diseases and it has become the major cause of cirrhosis in the Western world. The high prevalence of NAFLD-associated advanced liver disease reflects both the high prevalence of obesity-related fatty liver (hepatic steatosis) and the lack of specific treatments to prevent hepatic steatosis from progressing to more serious forms of liver damage, including nonalcoholic steatohepatitis (NASH), cirrhosis, and primary liver cancer. The pathogenesis of NAFLD is complex, and not fully understood. However, compelling evidence demonstrates that dysregulation of the hedgehog (Hh) pathway is involved in both the pathogenesis of hepatic steatosis and the progression from hepatic steatosis to more serious forms of liver damage. Inhibiting Hedgehog signaling enhances hepatic steatosis, a condition which seldom results in liver-related morbidity or mortality. In contrast, excessive Hedgehog pathway activation promotes development of NASH, cirrhosis, and primary liver cancer, the major causes of liver-related deaths. Thus, suppressing excessive Hh pathway activity is a potential approach to prevent progressive liver damage in NAFLD. Various pharmacologic agents that inhibit Hh signaling are available and approved for cancer therapeutics; more are being developed to optimize the benefits and minimize the risks of inhibiting this pathway. In this review we will describe the Hh pathway, summarize the evidence for its role in NAFLD evolution, and discuss the potential role for Hh pathway inhibitors as therapies to prevent NASH, cirrhosis and liver cancer.

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Hedgehog signaling is a potent regulator of liver lipid metabolism and reveals a GLI-code associated with steatosis

Cited by 64 publications

References 73 publications

Human germline hedgehog pathway mutations predispose to fatty liver

Human germline hedgehog pathway mutations predispose to fatty liver

Metabolic zonation of the liver: The oxygen gradient revisited

The hedgehog pathway in nonalcoholic fatty liver disease

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