Figures data source ATGL / SREBP-1c regulation.

Sterol Regulatory Element-Binding Protein-1c (SREBP-1c) is translated as an inactive precursor protein that is proteolytically cleavage-activated to promote fatty acid (FA) biosynthesis when unsaturated FAs (uFAs) are scarce. During fasting, however, lipogenesis is low, and adipose tissue lipolysis supplies the organism with FAs. Adipose Triglyceride Lipase (ATGL) is the rate-limiting enzyme for lipolysis in adipose tissue, and it preferentially releases uFAs. Therefore, we hypothesized that adipose ATGL-derived FAs suppress the proteolytic activation of SREBP-1c in the liver in a transitory manner after fasting. Indeed, we show that (I) SREBP-1c is hyper-activated in livers of adipose specific <i>Atgl</i> knockout mice after fasting and high carbohydrate refeeding. (II) This effect is reversed by injection of albumin bound uFAs. (III) uFAs inhibit Endoplasmic Reticulum to Golgi-apparatus transport of SREBP Cleavage-Activating Protein (SCAP) in hepatocytes, which is essential for SREBP cleavage-activation. Our findings demonstrate that adipose tissue ATGL derived uFAs attenuate SREBP‑1c cleavage-activation in the liver after fasting.