Acute intermittent hypoxia drives hepatic de novo lipogenesis in humans and rodents

• DOI: 10.1016/j.metop.2022.100177
• Publication Date: 2022-03-14T21:44:52Z
• Authors: Jonathan M. Hazle...; Teegan Reina Lim; Catriona Charlton; Jack J. Miller; Laura L. Gathercole; Thomas Cornfield; Nikolaos Nikolaou; Shelley E. Harris; Ahmad Moolla; Nantia Othonos; Lisa C. Heather; Thomas Marjot; Damian J. Tyler; Carolyn Carr; Leanne Hodson; Jane McKeating; Jeremy W. Tomlinson
• Keywords: Lipogenesis; Hypoxia; Intermittent hypoxia; Acetyl-CoA Carboxylase

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic condition. It tightly associated with an adverse metabolic phenotype (including obesity and type 2 diabetes) as well obstructive sleep apnoea (OSA) of which intermittent hypoxia a critical component. Hepatic de novo lipogenesis (DNL) significant contributor to hepatic lipid content pathogenesis NAFLD has been proposed key pathway target in development pharmacotherapies treat NAFLD. Our aim use experimental models investigate impact on metabolism independent disease. Human rodent studies incorporating stable isotopes hyperinsulinaemic euglycaemic clamp were performed assess regulation DNL broader by hypoxia. Cell-based studies, including pharmacological genetic manipulation hypoxia-inducible factors (HIF), used examine underlying mechanisms. increased response acute humans, without alteration glucose production or disposal. These observations endorsed prolonged model rodents using isotopic assessment metabolism. Changes paralleled increases gene expression acetyl CoA carboxylase 1 acid synthase. In human hepatoma cell lines, both uptake through HIF-1α -2α dependent provide robust evidence linking sustained vivo hypoxia, providing important mechanistic link between