Intestinal FGF15 regulates bile acid and cholesterol metabolism but not glucose and energy balance
(2024) JCI Insight — Vol. 9, n° 7, p. e174164 [1-21] (2024)
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Bozadjieva-Kramer, Nadejda 
Li, Ziru Rupp, Alan C. Seeley, Randy J.
- Abstract
- Fibroblast growth factor 15/19 (FGF15/19, mouse/human ortholog) is expressed in the ileal enterocytes of the small intestine and released postprandially in response to bile acid absorption. Previous reports of FGF15-/- mice have limited our understanding of gut-specific FGF15's role in metabolism. Therefore, we studied the role of endogenous gut-derived FGF15 in bile acid, cholesterol, glucose, and energy balance. We found that circulating levels of FGF19 were reduced in individuals with obesity and comorbidities, such as type 2 diabetes and metabolic dysfunction-associated fatty liver disease. Gene expression analysis of ileal FGF15-positive cells revealed differential expression during the obesogenic state. We fed standard chow or a high-fat metabolic dysfunction-associated steatohepatitis-inducing diet to control and intestine-derived FGF15-knockout (FGF15INT-KO) mice. Control and FGF15INT-KO mice gained similar body weight and adiposity and did not show genotype-specific differences in glucose, mixed meal, pyruvate, and glycerol tolerance. FGF15INT-KO mice had increased systemic bile acid levels but decreased cholesterol levels, pointing to a primary role for gut-derived FGF15 in regulating bile acid and cholesterol metabolism when exposed to obesogenic diet. These studies show that intestinal FGF15 plays a specific role in bile acid and cholesterol metabolism regulation but is not essential for energy and glucose balance.
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Bozadjieva-Kramer, N., Shin, J. H., Li, Z., Rupp, A. C., Miller, N., Kernodle, S., Lanthier, N., Henry, P., Seshadri, N., Myronovych, A., MacDougald, O. A., O’Rourke, R. W., Kohli, R., Burant, C. F., Rothberg, A. E., & Seeley, R. J. (2024). Intestinal FGF15 regulates bile acid and cholesterol metabolism but not glucose and energy balance. JCI Insight, 9(7), e174164 [1-21]. https://doi.org/10.1172/jci.insight.174164 (Original work published 2024)