Journal: Nature Communications

Article Title: Hepatocyte SLCO4C1 is a cAMP uptake transporter for inhibiting lipogenesis and a therapeutic target for MASLD

doi: 10.1038/s41467-026-70729-0

Figure Lengend Snippet: A Cytokines stimulated Slco4c1 mRNA transcription in primary mouse hepatocytes ( B ) FGF21 expression levels in different hepatic cell types. C Hepatic Fgf21 mRNA levels in GAN diet fed mice. D Correlation analysis between hepatic Fgf21 and Slco4c1 mRNA levels ( n = 6). E , F Treatment with FGF21 stimulated Slco4c1 mRNA and protein expression in primary mouse hepatocytes ( G ) Schematic illustration of the predicted transcription factors. H The predicted transcription factor mRNA transcripts in the FGF21-treated primary mouse hepatocytes. I , J Hepatic Egr1/2/3 mRNA transcripts and protein expression in the indicated groups of mice. (* p < 0.05, vs. Chow diet-WT) ( K ) Correlation between hepatic Slco4c1 and Egrs mRNA levels in the GAN diet-fed WT mice ( n = 6). L A diagram illustrating the potential EGRs binding sites in human SLCO4C1 proximal promoter and the reporter constructs. M Luciferase activities in 293 T cells co-transfected with truncated SLCO4C1 promoters with, or without, plasmids for EGRs overexpression. N A schematic diagram displayed the EGR1-binding site in the SLCO4C1 promoter and its mutant. O Luciferase activity in 293 T cells co-transfected with the mutant Slco4c1 promoter and the plasmid for EGR1 overexpression. Relative levels of Egr1 mRNA ( P ) and protein ( Q ) expression in primary mouse hepatocytes treated with, or without, an ERK/MAPK inhibitor, and after stimulated by FGF21 were examined. R ChIP assay revealed that FGF21 increased Egr1 binding to the Slco4c1 -59 promoters in primary mouse hepatocytes. Relative levels Slco4c1 mRNA (S) and protein (T) expression in primary mouse hepatocytes treated with, or without, an ERK/MAPK inhibitor, and after stimulated by FGF21 were examined. A n = 5 and M , O n = 3, Biological replicates; C , I , J Each dot represents one mouse sample; Statistics: unpaired two-tailed Student’s t test. R: n = 3 and E , F , H , P , Q , S , T n = 5, Biological replicates; Statistics: one-way ANOVA test, Multiple comparisons. *p < 0.05, * *p < 0.01, *** p < 0.001, **** p < 0.0001. F: * p < 0.05 vs. FGF21 0 μg/ml; # p < 0.05 vs. FGF21 0.1 μg/ml. Q, T: * p < 0.05 vs. FGF21 0 μg/ml; # p < 0.05 vs. FGF21 1 μg/ml. All data statistics are presented as mean ± SD and 95% confidence interval.

Article Snippet: After fasting for 12 h, HepG2 cells were treated with 375 μM PA (MCE, New Jersey, USA, Cat: HY-N0830) in a complete medium for 12 h or 24 h. The isolated primary mouse hepatocytes were cultured in 5% fetal bovine serum-Williams’ Medium E for 6-8 h, and subsequently treated with 250 μM PA for 12 h or 24 h. In addition, the cells were treated with different concentrations of FGF21 (SinoBiological, Beijing, China, Cat:10911-HNAE) for varying time periods and their viability was examined by CCK-8 assays using the specific kit (Bgbiotech, Chongqing, China, Cat: L2544823X).

Techniques: Expressing, Binding Assay, Construct, Luciferase, Transfection, Over Expression, Mutagenesis, Activity Assay, Plasmid Preparation, Two Tailed Test

Journal: Nature Communications

Article Title: Hepatocyte SLCO4C1 is a cAMP uptake transporter for inhibiting lipogenesis and a therapeutic target for MASLD

doi: 10.1038/s41467-026-70729-0

Figure Lengend Snippet: During the pathogenic process, metabolic disorder stimulates FGF21 expression, which through its receptors, activates the ERK/MAPK signaling to induce EGR1 expression. The transcription factor of EGR1 binds to the SLCO4C1 promoter and up-regulates its expression in hepatocytes. The SLCO4C1 functions as a cAMP uptake transporter through the interaction of its Gln463 with cAMP, increasing intracellular cAMP levels that activate the PKA-CREB signaling to feedback down-regulate SREBP1 and downstream ACC1, FASN and SCD1 expression, inhibiting fatty acid synthesis. Accordingly, induction of SLCO4C1 overexpression by AAV8-mediated hepatic SLCO4C1 expression and/or increasing intracellular cAMP levels by the Forskolin treatment effectively prevent and mitigate the progression of MASLD. Therefore, SLCO4C1 is a therapeutic target for MASLD. Conceivably, our findings may aid in the design of therapeutic strategies for treating MASLD.

Article Snippet: After fasting for 12 h, HepG2 cells were treated with 375 μM PA (MCE, New Jersey, USA, Cat: HY-N0830) in a complete medium for 12 h or 24 h. The isolated primary mouse hepatocytes were cultured in 5% fetal bovine serum-Williams’ Medium E for 6-8 h, and subsequently treated with 250 μM PA for 12 h or 24 h. In addition, the cells were treated with different concentrations of FGF21 (SinoBiological, Beijing, China, Cat:10911-HNAE) for varying time periods and their viability was examined by CCK-8 assays using the specific kit (Bgbiotech, Chongqing, China, Cat: L2544823X).

Techniques: Expressing, Over Expression