Metformin inefficiency to lower lipids in vitamin B12 deficient HepG2 cells is alleviated via adiponectin-AMPK axis

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Boachie, J, Zammit, V, Saravanan, P and Adaikalakoteswari, A ORCID: https://orcid.org/0000-0003-2974-3388, 2023. Metformin inefficiency to lower lipids in vitamin B12 deficient HepG2 cells is alleviated via adiponectin-AMPK axis. Nutrients, 15 (24): 5046. ISSN 2072-6643

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Official URL: https://doi.org/10.3390/nu15245046

Abstract

Background: Prolonged metformin treatment decreases vitamin B12 (B12) levels, whereas low B12 is associated with dyslipidaemia. Some studies have reported that metformin has no effect on intrahepatic triglyceride (TG) levels. Although AMP-activated protein kinase (AMPK) activation via adiponectin lowers hepatic TG content, its role in B12 deficiency and metformin has not been explored. We investigated whether low B12 impairs the beneficial effect of metformin on hepatic lipid metabolism via the AMPK-adiponectin axis.

Methods: HepG2 was cultured using custom-made B12-deficient Eagle's Minimal Essential Medium (EMEM) in different B12-medium concentrations, followed by a 24-h metformin/adiponectin treatment. Gene and protein expressions and total intracellular TG were measured, and radiochemical analysis of TG synthesis and seahorse mitochondria stress assay were undertaken.

Results: With low B12, total intracellular TG and synthesized radiolabelled TG were increased. Regulators of lipogenesis, cholesterol and genes regulating fatty acids (FAs; TG; and cholesterol biosynthesis were increased. FA oxidation (FAO) and mitochondrial function were decreased, with decreased pAMPKα and pACC levels. Following metformin treatment in hepatocytes with low B12, the gene and protein expression of the above targets were not alleviated. However, in the presence of adiponectin, intrahepatic lipid levels with low B12 decreased via upregulated pAMPKα and pACC levels. Again, combined adiponectin and metformin treatment ameliorated the low B12 effect and resulted in increased pAMPKα and pACC, with a subsequent reduction in lipogenesis, increased FAO and mitochondrion function.

Conclusions: Adiponectin co-administration with metformin induced a higher intrahepatic lipid-lowering effect. Overall, we emphasize the potential therapeutic implications for hepatic AMPK activation via adiponectin for a clinical condition associated with B12 deficiency and metformin treatment.

Item Type:	Journal article
Publication Title:	Nutrients
Creators:	Boachie, J., Zammit, V., Saravanan, P. and Adaikalakoteswari, A.
Publisher:	MDPI AG
Date:	8 December 2023
Volume:	15
Number:	24
ISSN:	2072-6643
Identifiers:	Number Type 10.3390/nu15245046 DOI 1844173 Other
Rights:	© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Divisions:	Schools > School of Science and Technology
Record created by:	Laura Ward
Date Added:	14 Dec 2023 09:28
Last Modified:	14 Dec 2023 09:28
URI:	https://irep.ntu.ac.uk/id/eprint/50541