Autophagy impairment in liver CD11c+ cells promotes non-alcoholic fatty liver disease through production of IL-23

• Published in: Nature communications Vol. 13; no. 1; p. 1440
• Main Authors: Galle-Treger, Lauriane, Helou, Doumet Georges, Quach, Christine, Howard, Emily, Hurrell, Benjamin P., Muench, German R. Aleman, Shafiei-Jahani, Pedram, Painter, Jacob D., Iorga, Andrea, Dara, Lily, Emamaullee, Juliet, Golden-Mason, Lucy, Rosen, Hugo R., Soroosh, Pejman, Akbari, Omid
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17-03-2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/21; 13/31; 14/19; 45/61; 45/91; 631/250/127; 631/250/262; 631/80/39; 64/60; 692/4020/4021/288; Animals; Autophagy; CD11c antigen; Diet, High-Fat - adverse effects; Epidemics; Fatty liver; Glucose; Glucose tolerance; Hepatocytes; Homeostasis; Humanities and Social Sciences; Insulin; Insulin resistance; Insulin Resistance - genetics; Interleukin 23; Interleukin-23 - metabolism; Intolerance; Liver; Liver - metabolism; Liver diseases; Mice; Mice, Inbred C57BL; multidisciplinary; Myeloid cells; Non-alcoholic Fatty Liver Disease - metabolism; Pathogenesis; Phenotypes; Science; Science (multidisciplinary); Therapeutic targets
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-29174-y

There has been a global increase in rates of obesity with a parallel epidemic of non-alcoholic fatty liver disease (NAFLD). Autophagy is an essential mechanism involved in the degradation of cellular material and has an important function in the maintenance of liver homeostasis. Here, we explore the effect of Autophagy-related 5 (Atg5) deficiency in liver CD11c
+
cells in mice fed HFD. When compared to control mice, Atg5-deficient CD11c
+
mice exhibit increased glucose intolerance and decreased insulin sensitivity when fed HFD. This phenotype is associated with the development of NAFLD. We observe that IL-23 secretion is induced in hepatic CD11c
+
myeloid cells following HFD feeding. We demonstrate that both therapeutic and preventative IL-23 blockade alleviates glucose intolerance, insulin resistance and protects against NAFLD development. This study provides insights into the function of autophagy and IL-23 production by hepatic CD11c
+
cells in NAFLD pathogenesis and suggests potential therapeutic targets.
The function of autophagy and how this affects non-alcoholic fatty liver disease is not fully known. Here the authors show that in mice with a targeted disruption of the autophagy pathway in CD11c
+
cells, development of NAFLD is accelerated involving IL-23 and blocking of IL-23 reduces disease.