Bradley Conn

Background: Non-alcoholic fatty liver disease (NAFLD) is a progressive disease in which fat abnormally accumulates (steatosis) in the liver.¹ NAFLD can progress to fibrosis, cirrhosis, hepatocellular carcinoma and potentially death.² The prevalence of NAFLD in the general population is 25%, in individuals with Type 2 Diabetes it is 60%, and it is 90% in morbidly obese individuals.² Overnutrition and sedentarism are thought to be major lifestyle causes of NAFLD.³ Current treatment typically consists of weight loss, dietary, and lifestyle changes. End stage liver disease can be treated with liver transplant. However, there are currently no approved direct therapeutics to treat the pathology of NAFLD.⁴

Objective: In this narrative review, we will examine if FXR agonism can improve pathology related to NAFLD via directly regulating hepatic lipid metabolism.

Search Methods: For this review, a search of PubMed was conducted of the time frame of 2017-2023, using MeSH/Keywords “NAFLD” “FXR Agonism” “Metabolic Pathways”

Results: Studies indicate that FXR agonism can decrease hepatic lipid levels in mice fed a high fat diet.⁵ FXR agonism has been shown, in mice, to decrease expression of the hepatic lipogenic proteins SREBP-1c, FAS, ACC1 and SCD1.⁵ Further, it was shown to increase the mRNA expression of the hepatic β-oxidation enzymes CPT1α, ACADS, and PPARα.⁵ FXR agonism has been shown to alter bile acid levels and composition, which directly decreased intestinal lipid absorption.⁶ FXR agonism has been demonstrated to decrease hepatic 1-deoxysphingolipids(1DOS), in mice.⁷ It was further shown to increase mRNA expression of CYP4f family of enzymes which are 1DOS degradation enzymes.⁷ FXR agonism has been demonstrated to protect the liver of mice from high fat diet induced steatosis and fibrosis, overall retaining a normal hepatic histological architecture, offering protection from NAFLD pathology.⁸ Early clinical trial data shows that FXR agonism provides clinically significant improvement to fibrosis and steatosis in patients diagnosed with NAFLD.⁹

Conclusions: Studies have shown that FXR agonism is able to decrease hepatic lipid levels in mice via directly downregulating hepatic lipogenesis, and intestinal lipid absorption, while upregulating hepatic β-oxidation. Further, FXR agonism has been shown to decrease hepatic 1DOS levels in mice by increasing the expression of degradation enzymes, protecting the liver from hepatotoxicity induced by ROS stress. It has been demonstrated that FXR agonism can protect the liver of mice from steatosis, and fibrosis induced by a high fat diet. The previously discussed mechanisms are theorized to be what provides this protection. Finally, ongoing clinical trials have shown that FXR agonism is able to provide clinically significant improvement to NAFLD induced pathology in humans. The evidence provided in this review supports the argument that FXR agonism “can” be used to improve NAFLD associated pathology. To expand upon this research the next question to be asked is “should” FXR agonism be used to treat NAFLD, and if so “in what circumstances?”

Works Cited:

1. Xi Y, Li H. Role of farnesoid X receptor in hepatic steatosis in nonalcoholic fatty liver disease. Biomed Pharmacother. 2020;121:109609. doi:10.1016/j.biopha.2019.109609
2. Younossi ZM. Non-alcoholic fatty liver disease – A global public health perspective. J Hepatol. 2019;70(3):531-544. doi:10.1016/j.jhep.2018.10.033
3. Stefan N, Häring HU, Cusi K. Non-alcoholic fatty liver disease: causes, diagnosis, cardiometabolic consequences, and treatment strategies. Lancet Diabetes Endocrinol. 2019;7(4):313-324. doi:10.1016/S2213-8587(18)30154-2
4. Singh S, Osna NA, Kharbanda KK. Treatment options for alcoholic and non-alcoholic fatty liver disease: A review. World J Gastroenterol. 2017;23(36):6549-6570. doi:10.3748/wjg.v23.i36.6549
5. Dong R, Yang X, Wang C, et al. Yangonin protects against non-alcoholic fatty liver disease through farnesoid X receptor. Phytomedicine. 2019;53:134-142. doi:10.1016/j.phymed.2018.09.006
6. Clifford BL, Sedgeman LR, Williams KJ, et al. FXR activation protects against NAFLD via bile-acid-dependent reductions in lipid absorption. Cell Metab. 2021;33(8):1671-1684.e4. doi:10.1016/j.cmet.2021.06.012
7. Gai Z, Gui T, Alecu I, et al. Farnesoid X receptor activation induces the degradation of hepatotoxic 1-deoxysphingolipids in non-alcoholic fatty liver disease. Liver Int. 2020;40(4):844-859. doi:10.1111/liv.14340
8. Marchianò S, Biagioli M, Morretta E, et al. Combinatorial therapy with BAR502 and UDCA resets FXR and GPBAR1 signaling and reverses liver histopathology in a model of NASH. Sci Rep. 2023;13(1):1602. Published 2023 Jan 28. doi:10.1038/s41598-023-28647-4
9. Younossi ZM, Ratziu V, Loomba R, et al. Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial [published correction appears in Lancet. 2020 Aug 1;396(10247):312] [published correction appears in Lancet. 2021 Jun 19;397(10292):2336]. Lancet. 2019;394(10215):2184-2196. doi:10.1016/S0140-6736(19)33041-7