Transcriptomics of natural and synthetic vitamin D in human hepatocyte lipotoxicity

Area of Science:

• Hepatology
• Molecular Biology
• Nutritional Science

Background:

• Nonalcoholic fatty liver disease (NAFLD) involves lipotoxicity and impaired vitamin D (VD) metabolism.
• The comparative effects of different VD formulations on liver cell lipotoxicity are not well understood.

Purpose of the Study:

• To compare the chemopreventive effects of a natural VD2 formulation (Shiitake Mushroom extract, SM-VD2) against synthetic VD3 (SV-VD3) and its active metabolite (1,25(OH)2-D3) in lipotoxic human liver cells.
• To investigate the distinct molecular mechanisms underlying the cytoprotective effects of these VD forms.

Main Methods:

• Human HepaRG liver cells were treated with oleic and palmitic acid to induce lipotoxicity.
• Cells were co-treated with SM-VD2, SV-VD3, or 1,25(OH)2-D3.
• Transcriptome analysis (gene expression profiling) and immunoblotting were employed to assess cellular responses and protein expression.

Main Results:

• All VD formulations effectively reduced lipotoxicity and transcriptomic alterations in liver cells.
• Distinct gene expression profiles were observed for each VD form, indicating diverse cytoprotective pathways.
• SM-VD2 and 1,25(OH)2-D3 showed significant gene homology, differing in the number and type of biological functions modulated.
• Protein analysis revealed differential responses of VDR and related proteins (FXR, PXR, PPARγ/PGC-1α, CYP3A4, CYP24A1) to natural versus synthetic VD.

Conclusions:

• Natural and synthetic Vitamin D formulations exhibit comparable efficacy in mitigating fatty liver lipotoxicity.
• The cytoprotective effects are driven by distinct cellular transcriptome responses and signaling pathways.
• Understanding these differential mechanisms is crucial for optimizing VD-based strategies against NAFLD.