Mechanisms into the development of fatty liver disease: role of bile acids, Betaine and MHY908

Khalid, Q. 2019. Mechanisms into the development of fatty liver disease: role of bile acids, Betaine and MHY908. PhD thesis University of Westminster Life Sciences

TitleMechanisms into the development of fatty liver disease: role of bile acids, Betaine and MHY908
TypePhD thesis
AuthorsKhalid, Q.
Abstract

Background: Non-alcoholic fatty liver disease (NAFLD) is an emerging epidemic worldwide. It is a metabolic condition that etiologically parallels with obesity, type 2 diabetes, and the metabolic syndrome. However, the pathogenesis of NAFLD remains elusive, though it is known free fatty acids such as palmitate promote liver injury. Therefore, there is a pressing need to find a potent therapeutic approach for NAFLD. Firstly, this study aimed to investigate the lipotoxicity and mitochondrial dysfunction attributable to palmitic acid. Subsequent investigations focused on investigating possible alternative therapies for NAFLD such as bile acids, betaine and a PPARα/γ dual agonist MHY908.

Method: Human hepatoma cell line, VL17A cells were treated with saturated fatty acid palmitic acid (PA) with a range of concentrations between 10 μM - 300 μM for 24 h, 48 h and 72 h after which lipid accumulation, cell toxicity, oxidative stress and mitochondrial function were assessed. Further investigations were employed with bile acids chenodeoxycholic acid (CDCA) and ursodeoxycholic acid (UDCA), betaine and MHY908 to determine whether lipotoxicity induced by PA would be attenuated and therefore could be a potential therapy for NAFLD.

Results: PA treatment showed a detrimental effect on cell viability in a time and dose dependant manner, where longer incubation time and higher concentrations of PA exhibited the greatest cytotoxicity. At 72 h, 300 μM PA led to a 90% decrease in cell viability (p < 0.001). Lipid accumulation also increased with higher doses, 250 μM PA treatment led to a 21% increase in lipid accumulation (p < 0.001). PA induced oxidative stress and mitochondrial dysfunction at higher concentration. At 300 μM PA treatment led to increases in ROS at 30 minutes (+46%, p <0.001) and 1 h (+61%, p <0.001). Lower PA doses 50 μM and 100 μM PA were employed in subsequent studies. UDCA exhibited hepatoprotective effects when co-incubated with PA predominantly at 24 h with 30 μM treatment; cell viability (UDCA +13%, p < 0.05), lipid accumulation (UDCA -47%, p < 0.001), ROS levels and mitochondrial function improved in all parameters investigated. CDCA showed less hepatoprotective effects in comparison to UDCA. Betaine 20μM displayed anti-oxidative properties and attenuated PA induced lipotoxicity as cell viability increased +41%, p < 0.001 but there was no significant effect on lipid accumulation. PPARα/γ dual agonist MHY908 also showed beneficial effect with 1 μM treatment where cell viability increased by 26% (P < 0.001), lipid accumulation decreased by 13% (p < 0.001), ROS generation had a less significant effect as levels decreased by 3% though mitochondrial function improved.

Conclusion: This study determined the saturated fatty acid PA induced cytotoxicity and lipid accumulation in hepatocytes. This may be due to the increased activity of the lipogenic pathway which consequently promotes oxidative stress and mitochondrial dysfunction. Alternative therapies such as UDCA, betaine and MHY908 attenuated PA induced lipotoxicity and improved mitochondrial function. However, further work aims to elucidate the protein expression and gene expression of transcriptional factors involved in the molecular pathways to gain a better understanding of fatty liver disease progression and development of novel therapies to treat NAFLD.

Year2019
File
File Access Level
Open (open metadata and files)
Publication dates
PublishedAug 2019

Permalink - https://westminsterresearch.westminster.ac.uk/item/v291w/mechanisms-into-the-development-of-fatty-liver-disease-role-of-bile-acids-betaine-and-mhy908


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