A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
IL-22 resolves MASLD via enterocyte STAT3 restoration of diet-perturbed intestinal homeostasis
Tekijät: Zhang P., Liu J., Lee A., Tsaur I., Ohira M., Duong V., Vo N., Watari K., Su H., Kim J.Y., Gu L., Zhu M., Shalapour S., Hosseini M., Bandyopadhyay G., Zeng S., Llorente C., Zhao H.N., Lamichhane S., Mohan S., Dorrestein P.C., Olefsky J.M., Schnabl B., Soroosh P., Karin M.
Kustantaja: Cell Press
Julkaisuvuosi: 2024
Journal: Cell Metabolism
Tietokannassa oleva lehden nimi: Cell metabolism
Vuosikerta: 36
Numero: 10
Aloitussivu: 2341
Lopetussivu: 2354
ISSN: 1550-4131
eISSN: 1932-7420
DOI: https://doi.org/10.1016/j.cmet.2024.08.012
Verkko-osoite: https://doi.org/10.1016/j.cmet.2024.08.012
Rinnakkaistallenteen osoite: https://research.utu.fi/converis/portal/detail/Publication/458532888
The exponential rise in metabolic dysfunction-associated steatotic liver disease (MASLD) parallels the ever-increasing consumption of energy-dense diets, underscoring the need for effective MASLD-resolving drugs. MASLD pathogenesis is linked to obesity, diabetes, "gut-liver axis" alterations, and defective interleukin-22 (IL-22) signaling. Although barrier-protective IL-22 blunts diet-induced metabolic alterations, inhibits lipid intake, and reverses microbial dysbiosis, obesogenic diets rapidly suppress its production by small intestine-localized innate lymphocytes. This results in STAT3 inhibition in intestinal epithelial cells (IECs) and expansion of the absorptive enterocyte compartment. These MASLD-sustaining aberrations were reversed by administration of recombinant IL-22, which resolved hepatosteatosis, inflammation, fibrosis, and insulin resistance. Exogenous IL-22 exerted its therapeutic effects through its IEC receptor, rather than hepatocytes, activating STAT3 and inhibiting WNT-β-catenin signaling to shrink the absorptive enterocyte compartment. By reversing diet-reinforced macronutrient absorption, the main source of liver lipids, IL-22 signaling restoration represents a potentially effective interception of dietary obesity and MASLD.
Ladattava julkaisu This is an electronic reprint of the original article. |  |
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Research was supported by grants from the NIH (R37AI043477 and R01DK133448 to M.K.; DK120515 to the SDDRC), Janssen Research & Development, the National Cancer Institute Cancer Center Support Grant (CCSG) (P30CA23100 to TTSR), and the UCSD School of Medicine Microscopy Core (NINDS P30-NS047101). This publication includes data generated at the UCSD IGM Genomics Center utilizing an Illumina NovaSeq 6000 that was purchased with funding from a National Institutes of Health SIG grant (#S10 OD026929).
