Adipose Triglyceride Lipase is needed for homeostatic control of Sterol Element-Binding Protein-1c driven hepatic lipogenesis

Wieser, B. I.; Pena de la Sancha, P.; Schauer, S.; Reicher, H.; Sattler, W.; Breinbauer, R.; Schweiger, M.; Espenshade, P. J.; Zechner, R.; Hoefler, G.; Vesely, P. W.

doi:10.1101/2020.11.02.363440

bioRxiv · 10.1101/2020.11.02.363440

Adipose Triglyceride Lipase is needed for homeostatic control of Sterol Element-Binding Protein-1c driven hepatic lipogenesis

Wieser, B. I.·Pena de la Sancha, P.·Schauer, S.·Reicher, H.·Sattler, W.·Breinbauer, R.·Schweiger, M.·Espenshade, P. J.·Zechner, R.·Hoefler, G.·Vesely, P. W.

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Abstract

Sterol Regulatory Element-Binding Protein-1c (SREBP-1c) is translated as an inactive precursor-protein that is proteolytically activated to promote fatty-acid (FA) biosynthesis, when unsaturated (u)FAs 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, and it preferentially hydrolyzes uFAs. Therefore, we hypothesized that ATGL-derived FAs may suppress the proteolytic activation of SREBP-1c in the liver. Here we show that (i) SREBP-1c is inactive during fasting but active after refeeding, (ii) uFA species liberated by ATGL suppress SREBP-1c activation in vitro, (iii) SREBP-1c is hyper-activated in livers of mice lacking ATGL, and (iv) pharmacological inhibition of ATGL selectively activates SREBP-1c in hepatocytes. Our findings highlight an ATGL/SREBP-1c axis, instrumental to coordinate lipogenesis and lipolysis, whose homeostatic regulation is crucial to avoid severe diseases including diabetes, cardiomyopathy, and even cancer.

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Wieser, B. I., Pena de la Sancha, P., Schauer, S., Reicher, H., Sattler, W., Breinbauer, R., Schweiger, M., Espenshade, P. J., Zechner, R., Hoefler, G., Vesely, P. W.. 2020-11-02. Adipose Triglyceride Lipase is needed for homeostatic control of Sterol Element-Binding Protein-1c driven hepatic lipogenesis. https://doi.org/10.1101/2020.11.02.363440

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