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Advancing MASLD & MASH Research: The Roles of LXRs, FXRs, and GP-BAR1 in Metabolic Regulation

Article from 2024-08-28

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Liver X receptors (LXRs), farnesoid X receptors (FXRs), and G protein-coupled bile acid receptors (GP-BAR, also known as TGR5) play crucial roles in regulating cholesterol, bile acid metabolism, and glucose homeostasis, making them intriguing approaches for therapeutic interventions in metabolic diseases like MASLD and MASH.

LXRs & Related Strategies to Target Cholesterol Homeostasis

Liver X receptors α/β (LXRα and LXRβ) are lipid-activated nuclear receptors that respond to sterol lipids and oxysterols to regulate fatty acid and cholesterol metabolism.¹^,² Because recent studies have suggested that cholesterol accumulation contributes to MASLD, agents targeting these receptors are of interest as therapeutic candidates. Hepatic free cholesterol accumulates due to excessive synthesis and reduced export/bile acid synthesis, a major pathway for the catabolism of hepatic cholesterol.³

LXRs have complex roles in many metabolic pathways and distinct differences occurring in a cell-type dependent manner.² Accordingly, LXR agonists, antagonists, and inverse agonists have been pursued as MASLD therapies. However, because of the multiple, complex roles of LXRs, strategies targeting LXRs may yield unintended consequences.

Some researchers are exploring alternative strategies to modify cholesterol synthesis by inhibiting HMG-CoA reductase, a major enzyme responsible for cholesterol synthesis enzyme, and/or sterol regulatory element binding proteins 1/2 (SREBP-1 and SREBP-2), which are regulatory factors that promote cholesterol synthesis.²

Effects of Targeting Cholesterol

Strategies to Target Cholesterol Homeostasis
Class	Effects	References
LXR agonists Activation of LXR regulates many aspects of metabolism, including carbohydrate, fatty acid, and cholesterol metabolism, but may be associated with increased lipogenesis and hepatic steatosis.	↑ Glycogenesis ↑ Hepatic cholesterol efflux ↑ Insulin secretion ↑ Insulin sensitivity ↓ Inflammation	¹^,²^,⁴
LXR antagonists and Inverse agonists Inhibiting LXR decreases de novo lipogenesis and inflammatory responses, blocking hepatic steatosis, inflammation, and liver fibrosis. However, LXR inhibition may be associated with cardiovascular diseases.	↓ De novo lipogenesis ↓ Hepatic steatosis ↓ Inflammation ↓ Liver fibrosis	¹^,²^,⁴
HMG-CoA reductase inhibitors HMG-CoA reductase inhibitors, known as 'statins', inhibit the activity of a key enzyme in cholesterol synthesis, thus reducing cholesterol levels.	↓ Hepatic cholesterol synthesis ↓ Liver injury indices ↓ Hepatic steatosis	^5,6

Item No.	Product Name	Description
15736	Human Liver X Receptors Reporter Assay Panel	A nuclear receptor cell-based reporter assay
15735	Human Liver X Receptor, Alpha Reporter Assay System	A nuclear receptor cell-based reporter assay
15734	Human Liver X Receptor, Beta Reporter Assay System	A nuclear receptor cell-based reporter assay

View all LXR cell-based reporter assays

Cholesterol Assay Kits

Item No.	Product Name	Description
10007640	Cholesterol Fluorometric Assay Kit	Quantitation of total cholesterol in plasma or serum
10010854	SREBP-1 Transcription Factor Assay Kit	A sensitive, non-radioactive method of detecting SREBP-1 from whole cell lysates
10007819	SREBP-2 Transcription Factor Assay Kit	A sensitive, non-radioactive method of detecting SREBP-2 from whole cell lysates

FXRs & Related Pathways to Target Bile Acid Signaling

Bile acids regulate lipid and glucose metabolism, and bile acid dysregulation contributes to metabolic dysfunction, inflammation, and liver injury in MASLD.⁷ Farnesoid X receptor (FXR) and G protein-coupled bile acid receptor (GP-BAR1), also known as Takeda G protein-coupled receptor 5 (TGR5), are the two main bile acid receptors. FXR and GP-BAR1 have become targets of therapies for MASLD given their roles as master regulators of carbohydrate and lipid metabolism, bile acid homeostasis, inflammation, and fibrosis—all of which may influence MASLD development.

Effects of Targeting Bile Acid Signaling

Strategies to Target Bile Acid Signaling
Class	Effects	References
FXR agonists Activation of FXR, a nuclear receptor highly expressed in the liver, intestine, and kidneys, has critical roles in carbohydrate and lipid metabolism and glucose homeostasis.	↓ De novo lipogenesis ↓ Hepatic lipid accumulation ↓ Plasma TGs and FFAs ↑ Fatty acid β-oxidation ↑ Glycogenesis ↑ Insulin sensitivity ↓ Inflammation	^8-11
GP-BAR1 agonists Activation of GP-BAR1, a G-protein coupled receptor highly expressed in skeletal muscle and adipose tissue, is associated with increased energy expenditure and glucose and lipid metabolism.	↑ GLP-1 secretion ↑ Insulin sensitivity ↓ Hepatic steatosis	⁸^,^12-14

Assay Kits for Bile Acid Signaling

Item No.	Product Name	Description
20349	Mouse Farnesoid X Receptor Reporter Assay System	A nuclear receptor cell-based reporter assay
15741	Human Farnesoid X Receptor Reporter Assay System	A nuclear receptor cell-based reporter assay
601440	TGR5 (GP-BAR1) Reporter Assay Kit	A reverse transfection reporter assay to screen for TGR5 agonists, antagonists, and modulators
41017	Human G Protein-Coupled Bile Acid Receptor 1 Reporter Assay System	A cell-based luciferase reporter assay for human GPBAR1

Bile Acids MaxSpec^® Discovery Mixture

A mixture of standards for the analysis of bile acids. The Bile Acids MaxSpec® Discovery Mixture contains primary and secondary bile acids, as well as glycine- and taurine-conjugated bile acids.

Taken together, the many roles of LXRs, FXRs, and GP-BAR1 in lipid and glucose metabolism makes them intriguing candidates for further study in MASLD and MASH research.

Lipidomics & Lipid Analysis Services

Cayman also offers a suite of services that may be of interest to MASLD and MASH researchers. Cayman's Lipidomics & Lipid Analysis Services offer researchers the opportunity to analyze lipid profiles in biological samples with our state-of-the-art facilities and of decades of collective expertise in lipid synthesis, purification, and characterization.

Analyses available for cholesterol esters and bile acids.

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Products for MASLD & MASH Research

The products featured in this series are a snapshot of the comprehensive resources available from Cayman for MASLD and MASH research. Our full catalog contains a comprehensive range of biochemicals, proteins, antibodies, and assay kits to support MASLD and MASH research.

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References

1. Griffett, K. and Burris, T.P. Development of LXR inverse agonists to treat MAFLD, NASH, and other metabolic diseases. Front. Med. (Lausanne) 10, 1102469 (2023).

2. Kim, H., Park, C., and Kim, T.H. Targeting liver X receptors for the treatment of non-alcoholic fatty liver disease. Cells 12(9), 1292 (2023).

3. Li, H., Yu, X.-H., Ou, X., et al. Hepatic cholesterol transport and its role in non-alcoholic fatty liver disease and atherosclerosis. Prog. Lipid Res. 83, 101109 (2021).

4. Ni, M., Zhang, B., Zhao, J., et al. Biological mechanisms and related natural modulators of liver X receptor in nonalcoholic fatty liver disease. Biomed. Pharmacother. 113, 108778 (2019).

5. Luo, J., Wang, J.-K., and Song, B.-L. Lowering low-density lipoprotein cholesterol: From mechanisms to therapies. Life Metab. 1(1), 25-38 (2022).

6. Boutari, C., Pappas, P.D., Anastasilakis, D., et al. Statins' efficacy in non-alcoholic fatty liver disease: A systematic review and meta-analysis. Clin. Nutr. 41(10), 2195-2206 (2022).

7. Groenen, C.C.J., Nguyen, T.-A., Paulusma, C.C., et al. Bile salt signaling and bile salt-based therapies in cardiometabolic disease. Clin. Sci. (Lond) 138(1), 1-21 (2024).

8. Almeqdadi, M. and Gordon, F.D. Farnesoid X receptor agonists: A promising therapeutic strategy for gastrointestinal diseases. Gastro. Hep. Adv. 3(3), 344-352 (2024).

9. Ali, A.H., Carey, E.J., and Lindor, K.D. Recent advances in the development of farnesoid X receptor agonists. Ann. Transl. Med. 3(1), 5 (2015).

10. Thomas, C., Gioiello, A., Noriega, L., et al. TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab. 10(3), 167-177 (2009).

11. Finn, P.D., Rodriguez, D., Kohler, J., et al. Intestinal TGR5 agonism improves hepatic steatosis and insulin sensitivity in Western diet-fed mice. Am. J. Physiol. Gastrointest. Liver Physiol. 316(3), G412-G424 (2019).

12. Lun, W., Yan, Q., Guo, X., et al. Mechanism of action of the bile acid receptor TGR5 in obesity. Acta Pharm. Sin. B 14(2), 468-491 (2024).

13. Mullur, R., Liu, Y.-Y., and Brent, G.A. Thyroid hormone regulation of metabolism. Physiol. Rev. 94(2), 355-382 (2014).

14. Kannt, A., Wohlfart, P., Madsen, A.N., et al. Activation of thyroid hormone receptor-β improved disease activity and metabolism independent of body weight in a mouse model of non-alcoholic steatohepatitis and fibrosis. Br. J. Pharmacol. 178(12), 2412-2423 (2021).

15. Karim, G. and Bansal, M.B. Resmetirom: An orally administered, small-molecule, liver-directed, β-selective THR agonist for the treatment of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. touchREV Endocrinol. 19(1), 60-70 (2023).

16. Hatziagelaki, E., Paschou, S.A., Schön, M., et al. NAFLD and thyroid function: Pathophysiological and therapeutic considerations. Trends Endocrinol. Metab. 33(11), 755-768 (2022).

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