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DOI: 10.1055/s-0030-1263392
Modulation of fibrogenic factors in hepatic stellate cells by Vitamin D and reduction of Vitamin D in NAFLD patients: Implications for NAFLD therapy
Introduction: Non-alcoholic fatty liver disease (NAFLD) is the most common hepatopathy and is closely associated with metabolic abnormalities. Patients with advanced liver disease exhibit vitamin-D (VD) deficiency. Our aim was to assess if VD influences primary hepatic stellate cells (HSC) phenotype and function, and possibly modulates NASH-associated fibrogenesis.
Methods: Primary human HSCs and LX2 immortalized human HSCs were treated with VD2 (10–6M) for 24h. Expression of α-SMA, COL1A, TGF-β, VDR, MCP-1, and IL-6 were determined by qRT-PCR and Western Blot (α-SMA, VDR). Metabolism of VD2 into 25VD2 was assayed in culture supernatants (25VD EIA-Kit) and 25VD in serum. Additionally, liver biopsies from 60 morbidly obese patients (BMI: 51.2±1.87; age: 45±1.98; 18 males/42 females) undergoing bariatric surgery were evaluated for fibrosis and intrahepatic expression of VDR. Patients were categorized as having NAFL (M30<275 U/ml) or NASH (>275 U/ml) by the M30 assay and compared with 10 healthy individuals.
Results: LX2 cells metabolized VD in a time-and concentration-dependent fashion. VD2 treatment significantly reduced expression of pro-fibrogenic factors (COL1α, α-SMA, TGF-β), proinflammatory cytokines (MCP-1, IL-6), and VDR after 24h in LX-2 and primary HSC. In NAFLD, especially in NASH patients, serum 25VD was significantly lower than in healthy individuals. Interestingly, NAFLD patients also exhibited higher VDR mRNA and protein expression compared to the control group, which was inversely correlated with liver fibrosis stage, as assessed by sirius red morphometry and serum hyaluronic acid levels.
Conclusion: VD depletion and elevated VDR expression correlate with NASH progression. Since VD represses VDR and profibrotic/proinflammatory cytokine expression in HSC, it may be a potentially useful treatment for individuals with advanced NASH.