IκBζ regulates the development of nonalcoholic fatty liver disease through the attenuation of hepatic steatosis in mice.

Hideki Ishikawa, Morisada Hayakawa, Nemekhbayar Baatartsogt, Nao Kakizawa, Hiromi Ohto-Ozaki, Takashi Maruyama, Kouichi Miura, Koichi Suzuki, Toshiki Rikiyama, Tsukasa Ohmori

Scientific reports 2022 Jul 08

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IκBζ is a transcriptional regulator that augments inflammatory responses from the Toll-like receptor or interleukin signaling. These innate immune responses contribute to the progression of nonalcoholic fatty liver disease (NAFLD); however, the role of IκBζ in the pathogenesis of NAFLD remains elusive. We investigated whether IκBζ was involved in the progression of NAFLD in mice. We generated hepatocyte-specific IκBζ-deficient mice (Alb-Cre; Nfkbizfl/fl) by crossing Nfkbizfl/fl mice with Alb-Cre transgenic mice. NAFLD was induced by feeding the mice a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD). CDAHFD-induced IκBζ expression in the liver was observed in Nfkbizfl/fl mice, but not in Alb-Cre; Nfkbizfl/fl mice. Contrary to our initial expectation, IκBζ deletion in hepatocytes accelerated the progression of NAFLD after CDAHFD treatment. Although the increased expression of inflammatory cytokines and apoptosis-related proteins by CDAHFD remained unchanged between Nfkbizfl/fl and Alb-Cre; Nfkbizfl/fl mice, early-stage steatosis of the liver was significantly augmented in Alb-Cre; Nfkbizfl/fl mice. Overexpression of IκBζ in hepatocytes via the adeno-associated virus vector attenuated liver steatosis caused by the CDAHFD in wild-type C57BL/6 mice. This preventive effect of IκBζ overexpression on steatosis was not observed without transcriptional activity. Microarray analysis revealed a correlation between IκBζ expression and the changes of factors related to triglyceride biosynthesis and lipoprotein uptake. Our data suggest that hepatic IκBζ attenuates the progression of NAFLD possibly through the regulation of the factors related to triglyceride metabolism. © 2022. The Author(s).

Citation

Hideki Ishikawa, Morisada Hayakawa, Nemekhbayar Baatartsogt, Nao Kakizawa, Hiromi Ohto-Ozaki, Takashi Maruyama, Kouichi Miura, Koichi Suzuki, Toshiki Rikiyama, Tsukasa Ohmori. IκBζ regulates the development of nonalcoholic fatty liver disease through the attenuation of hepatic steatosis in mice. Scientific reports. 2022 Jul 08;12(1):11634