ArticleCellular and molecular gastroenterology and hepatology2023
Hepatocyte Smoothened Activity Controls Susceptibility to Insulin Resistance and Nonalcoholic Fatty Liver Disease.
Article in Cellular and molecular gastroenterology and hepatology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 27 citations in OpenAlex.
- Estimated glucose disposal rate and markers of liver injury: A population-based study.Medicine · 2026Article
- Hepatocyte hedgehog signaling controls ferroptosis to alleviate aging-related organ dysfunction.JCI insight · 2026Article
- Mechanistic insights and evidence-based management of metabolic dysfunction-associated steatotic liver disease (MASLD; formerly NAFLD) through combined diet and exercise interventions: an evidence-based narrative review.Journal of clinical biochemistry and nutrition · 2026Review
- Mechanism elucidation of Polygonatum sibiricum-Prepared Cervus elaphus velvet antler in intervening non-alcoholic fatty liver disease based on network analysis combined with proteomics.Scientific reports · 2026Article
- Hepatocyte-targeted Bap1 reduction in the liver primes an inflammatory transcriptional response.G3 (Bethesda, Md.) · 2026Article
- Palmitoleic acid promoted by BMPR2 signaling primes CD169 macrophages and alleviates liver fibrosis.Communications biology · 2026Article
- Modulation of metabolic, inflammatory, fibrotic, and cell death pathways by resmetirom in metabolic dysfunction-associated steatohepatitis (MASH): a transcriptomic profiling study.Acta pharmacologica Sinica · 2026Article
- ADAR1 Controls Macrophage Scavenging and Lipid-Buffering Programs in Metabolic Tissues.European journal of immunology · 2026Article
- Anti-aging effect of Hedgehog signaling.Experimental & molecular medicine · 2026Review
- A novel palmitoylation-based molecular signature reveals COX6A1 as a key regulator in metabolic dysfunction-associated steatotic liver disease.Journal of translational medicine · 2025Article
- Targeting senescent hepatocytes for treatment of metabolic dysfunction-associated steatotic liver disease and multi-organ dysfunction.Nature communications · 2025Article
- EEF1A2 identified as a hub gene associated with the severity of metabolic dysfunction-associated steatotic liver disease.Mammalian genome : official journal of the International Mammalian Genome Society · 2025Article
- Targeting the gut microbiota and lipid metabolism: potential mechanisms of natural products for the treatment of non-alcoholic fatty liver disease.Frontiers in pharmacology · 2025Review
- CDT1 is a Potential Therapeutic Target for the Progression of NAFLD to HCC and the Exacerbation of Cancer.Current genomics · 2025Article
- Recent advances in non-alcoholic steatohepatitis-associated hepatocellular carcinoma: immune cells, metabolic dysregulation, and therapeutic strategies.Frontiers in oncology · 2025Review
- The Role of SHBG as a Marker in Male Patients with Metabolic-Associated Fatty Liver Disease: Insights into Metabolic and Hormonal Status.Journal of clinical medicine · 2024Article
- Hedgehog Signaling Pathway in Fibrosis and Targeted Therapies.Biomolecules · 2024Review
- Envisioning how to advance the MASH field.Nature reviews. Gastroenterology & hepatology · 2024Review
- The senescence-associated secretome of Hedgehog-deficient hepatocytes drives MASLD progression.The Journal of clinical investigation · 2024Article
- Aging promotes metabolic dysfunction-associated steatotic liver disease by inducing ferroptotic stress.Nature aging · 2024Article
Corrections and comments
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Authors and funding
15 authors at 4 institutions in 1 country.
Funding
Abstract
BACKGROUND &
aimsNonalcoholic steatohepatitis (NASH), a leading cause of cirrhosis, strongly associates with the metabolic syndrome, an insulin-resistant proinflammatory state that disrupts energy balance and promotes progressive liver degeneration. We aimed to define the role of Smoothened (Smo), an obligatory component of the Hedgehog signaling pathway, in controlling hepatocyte metabolic homeostasis and, thereby, susceptibility to NASH.
methodsWe conditionally deleted Smo in hepatocytes of healthy chow-fed mice and performed metabolic phenotyping, coupled with single-cell RNA sequencing (RNA-seq), to characterize the role of hepatocyte Smo in regulating basal hepatic and systemic metabolic homeostasis. Liver RNA-seq datasets from 2 large human cohorts were also analyzed to define the relationship between Smo and NASH susceptibility in people.
resultsHepatocyte Smo deletion inhibited the Hedgehog pathway and promoted fatty liver, hyperinsulinemia, and insulin resistance. We identified a plausible mechanism whereby inactivation of Smo stimulated the mTORC1-SREBP1c signaling axis, which promoted lipogenesis while inhibiting the hepatic insulin cascade. Transcriptomics of bulk and single Smo-deficient hepatocytes supported suppression of insulin signaling and also revealed molecular abnormalities associated with oxidative stress and mitochondrial dysfunction. Analysis of human bulk RNA-seq data revealed that Smo expression was (1) highest in healthy livers, (2) lower in livers with NASH than in those with simple steatosis, (3) negatively correlated with markers of insulin resistance and liver injury, and (4) declined progressively as fibrosis severity worsened.
conclusionsThe Hedgehog pathway controls insulin sensitivity and energy homeostasis in adult livers. Loss of hepatocyte Hedgehog activity induces hepatic and systemic metabolic stress and enhances susceptibility to NASH by promoting hepatic lipoxicity and insulin resistance.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.