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Hepatocyte Smoothened Activity Controls Susceptibility to Insulin Resistance and Nonalcoholic Fatty Liver Disease.

Publication ,  Conference
Chen, T; Dalton, G; Oh, S-H; Maeso-Diaz, R; Du, K; Meyers, RA; Guy, C; Abdelmalek, MF; Henao, R; Guarnieri, P; Pullen, SS; Gregory, S ...
Published in: Cell Mol Gastroenterol Hepatol
2023

BACKGROUND & AIMS: Nonalcoholic 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. METHODS: We 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. RESULTS: Hepatocyte 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. CONCLUSIONS: The 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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Published In

Cell Mol Gastroenterol Hepatol

DOI

EISSN

2352-345X

Publication Date

2023

Volume

15

Issue

4

Start / End Page

949 / 970

Location

United States

Related Subject Headings

  • Non-alcoholic Fatty Liver Disease
  • Mice
  • Insulin Resistance
  • Insulin
  • Humans
  • Hepatocytes
  • Hedgehog Proteins
  • Animals
  • Adult
  • 3202 Clinical sciences
 

Citation

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Chen, T., Dalton, G., Oh, S.-H., Maeso-Diaz, R., Du, K., Meyers, R. A., … Diehl, A. M. (2023). Hepatocyte Smoothened Activity Controls Susceptibility to Insulin Resistance and Nonalcoholic Fatty Liver Disease. In Cell Mol Gastroenterol Hepatol (Vol. 15, pp. 949–970). United States. https://doi.org/10.1016/j.jcmgh.2022.12.008
Chen, Tianyi, George Dalton, Seh-Hoon Oh, Raquel Maeso-Diaz, Kuo Du, Rachel A. Meyers, Cynthia Guy, et al. “Hepatocyte Smoothened Activity Controls Susceptibility to Insulin Resistance and Nonalcoholic Fatty Liver Disease.” In Cell Mol Gastroenterol Hepatol, 15:949–70, 2023. https://doi.org/10.1016/j.jcmgh.2022.12.008.
Chen T, Dalton G, Oh S-H, Maeso-Diaz R, Du K, Meyers RA, et al. Hepatocyte Smoothened Activity Controls Susceptibility to Insulin Resistance and Nonalcoholic Fatty Liver Disease. In: Cell Mol Gastroenterol Hepatol. 2023. p. 949–70.
Chen, Tianyi, et al. “Hepatocyte Smoothened Activity Controls Susceptibility to Insulin Resistance and Nonalcoholic Fatty Liver Disease.Cell Mol Gastroenterol Hepatol, vol. 15, no. 4, 2023, pp. 949–70. Pubmed, doi:10.1016/j.jcmgh.2022.12.008.
Chen T, Dalton G, Oh S-H, Maeso-Diaz R, Du K, Meyers RA, Guy C, Abdelmalek MF, Henao R, Guarnieri P, Pullen SS, Gregory S, Locker J, Brown JM, Diehl AM. Hepatocyte Smoothened Activity Controls Susceptibility to Insulin Resistance and Nonalcoholic Fatty Liver Disease. Cell Mol Gastroenterol Hepatol. 2023. p. 949–970.
Journal cover image

Published In

Cell Mol Gastroenterol Hepatol

DOI

EISSN

2352-345X

Publication Date

2023

Volume

15

Issue

4

Start / End Page

949 / 970

Location

United States

Related Subject Headings

  • Non-alcoholic Fatty Liver Disease
  • Mice
  • Insulin Resistance
  • Insulin
  • Humans
  • Hepatocytes
  • Hedgehog Proteins
  • Animals
  • Adult
  • 3202 Clinical sciences