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

Abstract

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.

The central inflammatory regulator IκBζ: induction, regulation and physiological functions

“…NFKBIZ rs645781 and NFKBIZ rs677011 have been closely associated with the risk of invasive pneumococcal disease (IPD) ( 152 ). Lipin1 coordinates liver metabolism, and IκBζ ameliorates fatty liver by downregulating Lipin1 ( 153 ). The NFKBIZ rs3217713 II genotype has been associated with a higher risk of death among COVID-19 patients with severe infection in the ICU ( 154 ).…”

Expression of IkappaB Family in the Ovine Liver during Early Pregnancy

“…IκBζ-dependent genes include IL-6 and lipocalin-2 that contribute to controlling acute hepatitis and bacterial infection [ 56 ]. Hepatic IκBζ regulates the factors related to triglyceride metabolism, which attenuates the progression of non-alcoholic fatty liver disease in mice [ 57 ]. Galectin-1 can downregulate IκBζ in the primary cultures of decidua cells, which is related with downregulation of the inflammatory response and the abundance of anti-inflammatory molecules during gestation [ 58 ].…”

NFKBIZ regulates NFκB signaling pathway to mediate tumorigenesis and metastasis of hepatocellular carcinoma by direct interaction with TRIM16

“…Relative research of bladder cancer showed NFKBIZ exerted an antitumoral effect by modulating PTEN/PI3K/Akt signaling pathway [ 11 ]. Previous researches have also indicated the intimate correlation between dysregulated expression of NFKBIZ and liver diseases such as acute hepatitis, nonalcoholic fatty liver disease and HBV- related HCC [ 12 , 13 ]. Mechanistically, NFKBIZ downregulation can suppress the expression of IL-6 (a hepatoprotective cytokine) and resulted in restricted inhibition of hepatitis; NFKBIZ can also regulate triglyceride metabolism to attenuate the progression of nonalcoholic fatty liver disease.…”