Abstract
FXR agonists are used to treat non-alcoholic fatty liver disease (NAFLD), in part because they reduce hepatic lipids. Here, we show that FXR activation with the FXR agonist GSK2324 controls hepatic lipids via reduced absorption and selective decreases in fatty acid synthesis. Using comprehensive lipidomic analyses, we show that FXR activation in mice or humans specifically reduces hepatic levels of mono- and polyunsaturated fatty acids (MUFA and PUFA). Decreases in MUFA are due to FXR-dependent repression of Scd1, Dgat2, and Lpin1 expression, which is independent of SHP and SREBP1c. FXR-dependent decreases in PUFAs are mediated by decreases in lipid absorption. Replenishing bile acids in the diet prevented decreased lipid absorption in GSK2324-treated mice, suggesting that FXR reduces absorption via decreased bile acids. We used tissue-specific FXR KO mice to show that hepatic FXR controls lipogenic genes, whereas intestinal FXR controls lipid absorption. Together, our studies establish two distinct pathways by which FXR regulates hepatic lipids.
| Original language | English |
|---|---|
| Pages (from-to) | 1671-1684.e4 |
| Number of pages | 19 |
| Journal | Cell Metabolism |
| Volume | 33 |
| Issue number | 8 |
| DOIs | |
| Publication status | Published - 3 Aug 2021 |
Keywords
- bile acids
- FXR
- intestinal lipid absorption
- NAFLD
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In: Cell Metabolism, Vol. 33, No. 8, 03.08.2021, p. 1671-1684.e4.
Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - FXR activation protects against NAFLD via bile-acid-dependent reductions in lipid absorption
AU - Clifford, Bethan L.
AU - Sedgeman, Leslie R.
AU - Williams, Kevin J.
AU - Morand, Pauline
AU - Cheng, Angela
AU - Jarrett, Kelsey E.
AU - Chan, Alvin P.
AU - Brearley-Sholto, Madelaine C.
AU - Wahlström, Annika
AU - Ashby, Julianne W.
AU - Barshop, William
AU - Wohlschlegel, James
AU - Calkin, Anna C.
AU - Liu, Yingying
AU - Thorell, Anders
AU - Meikle, Peter J.
AU - Drew, Brian G.
AU - Mack, Julia J.
AU - Marschall, Hanns Ulrich
AU - Tarling, Elizabeth J.
AU - Edwards, Peter A.
AU - de Aguiar Vallim, Thomas Q.
N1 - Funding Information: We thank Michelle Steel, Joan Cheng, and Elizabeth Vanderwall for help with mice. We thank all members of the Tarling-Vallim, Edwards, Tontonoz, and Bensinger labs at UCLA for useful advice and discussion and sharing reagents and resources. We thank David Deaton and Tim Willson for the generous gift of GSK2324. The graphical abstract was created using BioRender.com. B.L.C. was sponsored by an AHA post-doctoral fellowship 19POST34380145. L.R.S. was funded by a diversity supplement to NIH R01 DK112119 and T32EB027629. K.E.J. is sponsored by a UCLA Vascular Biology T32HL069766. A.P.C. is funded by T32DK007180. M.C.B.-S. is funded by an AHA post-doctoral fellowship (836561). H.U.M. is funded by grants from the Swedish Research Council (2013-2569/2016-01125) and the Swedish state under the agreement between the Swedish Government and the county councils and the ALF agreement (ALFGBG-426741/717321). A.T. is financially supported by grants from the Erling-Persson Family Foundation (140604). B.G.D. is funded by an Australian Heart Foundation Future Leader Fellowship (101789). J.J.M. is sponsored by an AHA Career Development award (19CDA34760007). E.J.T. is funded by NIH grants HL118161 and HL136543, E.J.T. and T.Q.d.A.V. are funded by NIH grant DK128952, T.Q.d.A.V. is funded by NIH grants HL122677 and DK119112, and P.A.E. and T.Q.d.A.V. are sponsored by NIH grant DK118064. T.Q.d.A.V. E.J.T. and P.A.E. oversaw and supervised the projects. Mouse experiments were performed by B.L.C. L.R.S. K.E.J. and A.C. Lipidomic analyses were performed by K.J.W. at the UCLA lipidomics core except for one study, which was performed by Y.L. A.C.C. B.G.D. and P.J.M. Radiolabeled absorption studies were performed by L.R.S. Bodipy-labeling study tissue processing, imaging, and quantification were performed by L.R.S. J.W.A. and J.J.M. Bile analysis by LC-MS was performed by L.R.S. M.C.B.-S. and W.B. under the supervision of J.W. GC-MS analyses were performed by P.M. and B.L.C. Sample collection and preparation for GC-MS were performed by B.L.C. A.P.C. and K.E.J. Human samples were collected by A.T. A.W. and H.U.M. Data analysis and statistical analyses were performed by B.L.C. L.R.S. and T.Q.d.A.V. Figures were generated by B.L.C. L.R.S. and T.Q.d.A.V. The manuscript was written by B.L.C. P.A.E. and T.Q.d.A.V. All authors revised and approved the final manuscript. The authors declare no competing interests. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in science. One or more of the authors of this paper received support from a program designed to increase minority representation in science. Funding Information: We thank Michelle Steel, Joan Cheng, and Elizabeth Vanderwall for help with mice. We thank all members of the Tarling-Vallim, Edwards, Tontonoz, and Bensinger labs at UCLA for useful advice and discussion and sharing reagents and resources. We thank David Deaton and Tim Willson for the generous gift of GSK2324. The graphical abstract was created using BioRender.com . B.L.C. was sponsored by an AHA post-doctoral fellowship 19POST34380145 . L.R.S. was funded by a diversity supplement to NIH R01 DK112119 and T32EB027629 . K.E.J. is sponsored by a UCLA Vascular Biology T32HL069766 . A.P.C. is funded by T32DK007180 . M.C.B.-S. is funded by an AHA post-doctoral fellowship ( 836561 ). H.U.M. is funded by grants from the Swedish Research Council ( 2013-2569/2016-01125 ) and the Swedish state under the agreement between the Swedish Government and the county councils and the ALF agreement ( ALFGBG-426741/717321 ). A.T. is financially supported by grants from the Erling-Persson Family Foundation ( 140604 ). B.G.D. is funded by an Australian Heart Foundation Future Leader Fellowship (101789). J.J.M. is sponsored by an AHA Career Development award ( 19CDA34760007 ). E.J.T. is funded by NIH grants HL118161 and HL136543 , E.J.T. and T.Q.d.A.V. are funded by NIH grant DK128952 , T.Q.d.A.V. is funded by NIH grants HL122677 and DK119112 , and P.A.E. and T.Q.d.A.V. are sponsored by NIH grant DK118064 . Publisher Copyright: © 2021 Elsevier Inc.
PY - 2021/8/3
Y1 - 2021/8/3
N2 - FXR agonists are used to treat non-alcoholic fatty liver disease (NAFLD), in part because they reduce hepatic lipids. Here, we show that FXR activation with the FXR agonist GSK2324 controls hepatic lipids via reduced absorption and selective decreases in fatty acid synthesis. Using comprehensive lipidomic analyses, we show that FXR activation in mice or humans specifically reduces hepatic levels of mono- and polyunsaturated fatty acids (MUFA and PUFA). Decreases in MUFA are due to FXR-dependent repression of Scd1, Dgat2, and Lpin1 expression, which is independent of SHP and SREBP1c. FXR-dependent decreases in PUFAs are mediated by decreases in lipid absorption. Replenishing bile acids in the diet prevented decreased lipid absorption in GSK2324-treated mice, suggesting that FXR reduces absorption via decreased bile acids. We used tissue-specific FXR KO mice to show that hepatic FXR controls lipogenic genes, whereas intestinal FXR controls lipid absorption. Together, our studies establish two distinct pathways by which FXR regulates hepatic lipids.
AB - FXR agonists are used to treat non-alcoholic fatty liver disease (NAFLD), in part because they reduce hepatic lipids. Here, we show that FXR activation with the FXR agonist GSK2324 controls hepatic lipids via reduced absorption and selective decreases in fatty acid synthesis. Using comprehensive lipidomic analyses, we show that FXR activation in mice or humans specifically reduces hepatic levels of mono- and polyunsaturated fatty acids (MUFA and PUFA). Decreases in MUFA are due to FXR-dependent repression of Scd1, Dgat2, and Lpin1 expression, which is independent of SHP and SREBP1c. FXR-dependent decreases in PUFAs are mediated by decreases in lipid absorption. Replenishing bile acids in the diet prevented decreased lipid absorption in GSK2324-treated mice, suggesting that FXR reduces absorption via decreased bile acids. We used tissue-specific FXR KO mice to show that hepatic FXR controls lipogenic genes, whereas intestinal FXR controls lipid absorption. Together, our studies establish two distinct pathways by which FXR regulates hepatic lipids.
KW - bile acids
KW - FXR
KW - intestinal lipid absorption
KW - NAFLD
UR - http://www.scopus.com/inward/record.url?scp=85111318477&partnerID=8YFLogxK
U2 - 10.1016/j.cmet.2021.06.012
DO - 10.1016/j.cmet.2021.06.012
M3 - Article
C2 - 34270928
AN - SCOPUS:85111318477
SN - 1550-4131
VL - 33
SP - 1671-1684.e4
JO - Cell Metabolism
JF - Cell Metabolism
IS - 8
ER -