Non-alcoholic Fatty Liver Disease and Cyclodextrins

 Non-alcoholic fatty liver disease and Cyclodextrins

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease with no currently approved efficacious treatment. (1) The disease is characterized by the accumulation of triglycerides in hepatocytes, comprises a broad spectrum of disorders ranging from simple liver steatosis (a condition in which fat accumulates in the liver cells), to non-alcoholic steatohepatitis with increasing inflammation and fibrosis. There are accumulating evidences that describe NAFLD as a complex, multisystem disease, which increases the risk of several related chronic diseases, such us type 2 diabetes, cardiovascular diseases, chronic kidney disease, and even cancer. The NAFLD has become a globally rising issue that can cause severe liver-related morbidity and mortality.

Non-alcoholic fatty liver disease (source: Shutterstock images)

Numerous studies have revealed that a high-fat diet largely contributes to the prevalence and progression of NAFLD via impacting gut microbiota and lipid metabolism signal pathways. (2) A recent publication communicates on the utility hydroxypropyl-beta-cyclodextrin-enabled resveratrol as a promising therapeutic tool to prevent and slow down NAFLD by activating the AMPK signaling pathway.(3)

Briefly about AMPK

AMPK is an abbreviation of Adenosin Mono-Phosphate-activated protein Kinase, is a central regulator of energy homeostasis, which coordinates metabolic pathways and thus balances nutrient supply with energy demand. Because of the favorable physiological outcomes of AMPK activation on metabolism, AMPK has been considered to be an important therapeutic target for controlling human diseases including metabolic syndrome and cancer. Therefore, activators of AMPK may have the potential as novel therapeutics for these diseases. (4)

Resveratrol, a natural bioactive compound, has been known to have potential for preventing and alleviating NAFLD. (5)  However, because of the poor aqueous solubility and oral bioavailability of resveratrol, its strengths and underlying mechanisms for NAFLD therapeutic potential are poorly understood. To address this, scientists in the recent paper described utility of 2-hydroxypropyl-beta-cyclodextrin (HPBCD) to enhance resveratrol’s water solubility and conducted disease-prevention and intervention experiments, in high fat diet-fed mice. The results showed that HPBCD significantly enhanced the water solubility of resveratrol and resveratrol-HPBCD complex was found to better prevent and alleviate the liver steatosis, obesity and abnormal lipid metabolism induced by high fat diet, than uncomplexed resveratrol, and slowed down progression of NAFLD. Further investigation indicated that the way resveratrol showed liver protective action, was due to modulation of gut microbiota. This microbiome modulation resulted in the elevation of the short-chain fatty acids levels and the activation of AMP-activated protein kinase signaling pathway. From the results of this experiment it was concluded that cyclodextrin-solubilized resveratrol beneficially modulated gut microbiota, altered gut microbiota-derived short chain fatty acids, and activated lipid metabolism regulatory pathways, providing potential for prevention and alleviation of NAFLD.

Comment: Author of this blog message is convinced that the remarkably positive outcome of the HPBCD-enabled resveratrol treatment was NOT exclusively due to the therapeutic potential of the AMPK activator, resveratrol. The presence of the solubilizing cyclodextrin derivative is probably an „added value” component of the treatment formulation, and is assumed to actively contribute (though not proven and discussed in the article) to the recorded treatment efficacy in non-alcoholic fatty liver disease. To support my thoughts behind this comment, I refer to some selected earlier publications describing that cyclodextrins affect AMPK-signaling pathways (6,7) and modulate gut microbiota (8, 9).

References:

1. Younossi, Z.M. Non-alcoholic fatty liver disease – A global public health perspective, J Hepatol. 70(3), 531-544 (2019). https://doi.org/10.1016/j.jhep.2018.10.033.
2. Lazarus, J.V., Mark, H.E., Anstee, Q.M. et al. Advancing the global public health agenda for NAFLD: a consensus statement. Nat. Rev. Gastroenterol. Hepatol. 19, 60–78 (2022). https://doi.org/10.1038/s41575-021-00523-4
3. Ke, W. et al. Hydroxypropyl-beta-Cyclodextrin embedded resveratrol regulates gut microbiota to prevent NAFLD via activating AMPK signaling pathway Food Bioscience 54,102907 (2023). https://doi.org/10.1016/j.fbio.2023.102907
4. Kim, J., Yang, G., Kim, Y. et al. AMPK activators: mechanisms of action and physiological activities. Exp. Mol. Med. 48, e224 (2016). https://doi.org/10.1038/emm.2016.16
5. Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444(7117), 337-42 (2006). https://doi.org/10.1038/nature05354.
6. Dai S, et al Methyl-β-cyclodextrin restores impaired autophagy flux in Niemann-Pick C1-deficient cells through activation of AMPK. Autophagy. 13(8), 1435-1451 (2017) https://doi.org/10.1080/15548627.2017.1329081.
7. Li X, Wang L, Zhou XE, Ke J, de Waal PW, Gu X, Tan MH, Wang D, Wu D, Xu HE, Melcher K. Structural basis of AMPK regulation by adenine nucleotides and glycogen. Cell Res. 25(1), 50-66 (2015). https://doi.org/10.1038/cr.2014.150
8. Zhu T, Zhang B, Feng Y, et al. Beneficial Effects of Three Dietary Cyclodextrins on Preventing Fat Accumulation and Remodeling Gut Microbiota in Mice Fed a High-Fat Diet. Foods. 11(8),1118. (2022). https://doi.org/10.3390/foods11081118
9. Nihei N, Okamoto H, Furune T, et al. Dietary α-cyclodextrin modifies gut microbiota and reduces fat accumulation in high-fat-diet-fed obese mice. Biofactors. 2018 May 7. https://doi.org/10.1002/biof.1429

Featured picture: https://www.medicalnewstoday.com/articles/322300