Restoration of mRNA Expression of Solute Carrier Proteins in Liver of Diet-Induced Obese Mice by Metformin

Abstract

Metformin (MET), the most common medicine for type 2 diabetes (T2DM), improves insulin sensitivity by targeting the liver, intestine and other organs. Its impact on expression of the solute carrier (Slc) transporter genes have not been reported in the mechanism of insulin sensitization. In this study, we examined Slc gene expression in the liver and colon of diet-induced obese (DIO) mice treated with MET by transcriptomic analysis. There were 939 differentially expressed genes (DEGs) in the liver of DIO mice vs lean mice, which included 34 Slc genes. MET altered 489 DEGs in the liver of DIO mice, in which 23 were Slc genes. Expression of 20 MET-responsive Slc DEGs was confirmed by qRT-PCR, in which 15 Slc genes were altered in DIO mice and their expressions were restored by MET, including Slc2a10, Slc2a13, Slc5a9, Slc6a14, Slc7a9, Slc9a2, Slc9a3, Slc13a2, Slc15a2, Slc26a3, Slc34a2, Slc37a1, Slc44a4, Slc51b and Slc52a3. While, there were only 97 DEGs in the colon of DIO mice with 5 Slc genes, whose expression was not restored by MET. The data suggest that more genes were altered in the liver over the colon by the high fat diet (HFD). There were 20 Slc genes with alteration confirmed in the liver of DIO mice and 15 of them were restored by MET, which was associated with improvement of insulin sensitivity and obesity. The restoration may improve the uptake of glucose, amino acids, mannose, fructose, 1,5-anhydro-D-glucitol and bumetanide in hepatocytes of the liver of DIO mice. The study provides new insight into the mechanism of metformin action in insulin sensitization and obesity.

Metabolic basis of solute carrier transporters in treatment of type 2 diabetes mellitus

“…Moreover, the expression of certain SLC genes in the liver of obese mice was found to be altered and restored by metformin treatment. This observation provides new insights into the mechanism of metformin in insulin sensitization and obesity 187 .…”

Genetic risk score for insulin resistance based on gene variants associated to amino acid metabolism in young adults

“…However, to our knowledge, there are no studies reporting an association between rs1007160 and IR. Lower expression of amino acid transporters, including SLC7A9, has been observed in hepatocytes from mice with diet-induced obesity, and this decrease was associated with hepatic steatosis, hyperlipidemia, obesity, and IR [ 49 , 50 ]. As a non-synonymous SNP, rs1007160 could potentially impact the structure or function of the transporter [ 51 ], resulting in a lower uptake of amino acids such as arginine and potentially affecting regulatory mechanisms.…”

Membrane transporters in cell physiology, cancer metabolism and drug response

“…Beyond inborn errors of metabolism, several SLCs have been associated with predisposition to or increased severity of multi-factorial diseases (reviewed previously by Lin et al, 2015 ), such as type II diabetes ( Barragán-Álvarez et al, 2021 ), hypertension ( Boedtkjer et al, 2011 ; International Consortium for Blood Pressure Genome-Wide Association Studies et al, 2011 ), obesity ( Le et al, 2021 ; Hodges et al, 2022 ), depression ( Santarelli et al, 2015 ), cancer ( Nimmanon et al, 2017 ; Fang et al, 2021 ; Han et al, 2021 ; Mao et al, 2021 ) and aging ( Crocco et al, 2018 ). For example, at synapses and in astroglia, the SLC1 ( Xu et al, 2016 ) and SLC6 ( Kristensen et al, 2011 ) families of amino acid transporters are responsible for the removal of neurotransmitters from the synaptic cleft, quenching postsynaptic effects after neurotransmission, and balancing excitatory and inhibitory neurotransmitters ( Aykac and Sehirli, 2020 ).…”

“…In turn, the redox and energetic status of a cell can influence the SLC expression profile to enable cells to exploit the availability of extracellular nutrients. For example, metformin treatment alters the expression of SLCs transporting substrates ranging from Zn 2+ and Cl − to glycerol-3-phosphate and amino acids ( Le et al, 2021 ), which underscores the metabolic impact of this drug. In fact, the significance of nutrient import in relation to cellular metabolic state is highly evolutionarily conserved.…”