TY - JOUR
T1 - IL32 downregulation lowers triglycerides and type I collagen in di-lineage human primary liver organoids
AU - Sasidharan, Kavitha
AU - Caddeo, Andrea
AU - Jamialahmadi, Oveis
AU - Noto, Francesca Rita
AU - Tomasi, Melissa
AU - Malvestiti, Francesco
AU - Ciociola, Ester
AU - Tavaglione, Federica
AU - Mancina, Rosellina M.
AU - Cherubini, Alessandro
AU - Bianco, Cristiana
AU - Mirarchi, Angela
AU - Männistö, Ville
AU - Pihlajamäki, Jussi
AU - Kärjä, Vesa
AU - Grimaudo, Stefania
AU - Luukkonen, Panu K.
AU - Qadri, Sami
AU - Yki-Järvinen, Hannele
AU - Petta, Salvatore
AU - Manfrini, Silvia
AU - Vespasiani-Gentilucci, Umberto
AU - Bruni, Vincenzo
AU - Valenti, Luca
AU - Romeo, Stefano
N1 - Publisher Copyright:
© 2023 The Author(s)
PY - 2024/1/16
Y1 - 2024/1/16
N2 - Steatotic liver disease (SLD) prevails as the most common chronic liver disease yet lack approved treatments due to incomplete understanding of pathogenesis. Recently, elevated hepatic and circulating interleukin 32 (IL-32) levels were found in individuals with severe SLD. However, the mechanistic link between IL-32 and intracellular triglyceride metabolism remains to be elucidated. We demonstrate in vitro that incubation with IL-32β protein leads to an increase in intracellular triglyceride synthesis, while downregulation of IL32 by small interfering RNA leads to lower triglyceride synthesis and secretion in organoids from human primary hepatocytes. This reduction requires the upregulation of Phospholipase A2 group IIA (PLA2G2A). Furthermore, downregulation of IL32 results in lower intracellular type I collagen levels in di-lineage human primary hepatic organoids. Finally, we identify a genetic variant of IL32 (rs76580947) associated with lower circulating IL-32 and protection against SLD measured by non-invasive tests. These data suggest that IL32 downregulation may be beneficial against SLD.
AB - Steatotic liver disease (SLD) prevails as the most common chronic liver disease yet lack approved treatments due to incomplete understanding of pathogenesis. Recently, elevated hepatic and circulating interleukin 32 (IL-32) levels were found in individuals with severe SLD. However, the mechanistic link between IL-32 and intracellular triglyceride metabolism remains to be elucidated. We demonstrate in vitro that incubation with IL-32β protein leads to an increase in intracellular triglyceride synthesis, while downregulation of IL32 by small interfering RNA leads to lower triglyceride synthesis and secretion in organoids from human primary hepatocytes. This reduction requires the upregulation of Phospholipase A2 group IIA (PLA2G2A). Furthermore, downregulation of IL32 results in lower intracellular type I collagen levels in di-lineage human primary hepatic organoids. Finally, we identify a genetic variant of IL32 (rs76580947) associated with lower circulating IL-32 and protection against SLD measured by non-invasive tests. These data suggest that IL32 downregulation may be beneficial against SLD.
KW - downregulation
KW - fatty liver disease
KW - FLD
KW - liver fibrosis
KW - minor allele
KW - natural killer cell transcript 4
KW - NIT
KW - NK4
KW - non-invasive test
KW - primary liver organoid
KW - SLD
KW - spheroids
KW - steatotic liver disease
KW - triglyceride
KW - 3121 General medicine, internal medicine and other clinical medicine
U2 - 10.1016/j.xcrm.2023.101352
DO - 10.1016/j.xcrm.2023.101352
M3 - Article
SN - 2666-3791
VL - 5
JO - Cell Reports Medicine
JF - Cell Reports Medicine
IS - 1
M1 - 101352
ER -