Vitamin D deficiency promotes nonalcoholic steatohepatitis through impaired enterohepatic circulation in animal model

Abstract

Vitamin D deficiency (VDD) or insufficiency is recognized for its association with nonalcoholic steatohepatitis (NASH), whereas the underlying mechanism remains unknown. Using animal models, we found that vitamin D deficiency promoted the high-fat diet (HFD)-initiated simple steatosis into typical NASH, characterized by elevated hepatic inflammation and fat degeneration. The NASH derived from VDD + HFD was related to poor retention of bile acids in the liver and biliary tree, in line with downregulation of the ileal apical sodium-dependent bile acid cotransporter (iASBT). The impediment of hepatic bile acids by the VDD + HFD mice was related to increased expression of hepatic SREBP-1c and fatty acid synthase, suggesting that VDD may upregulate endogenous fatty acid synthesis into NASH through impaired enterohepatic circulation. Administration of 1,25(OH)2VD3 (calcitriol) corrected the NASH phenotypes in line with restoration of iASBT, promotion of bile filling in the biliary tree, suppression of hepatic lipogenesis, and inflammation. Moreover, administration of a bile acid-sequestering agent suppressed ileal fibroblast growth factor 15 expression, leading to increased iASBT expression to restore bile filling in the liver and biliary tree, which ameliorates steatosis and inflammation in the liver. These results suggest a novel mechanism for NASH development, by which VDD downregulates iASBT expression, resulting in a poor bile acid pool and elevation of hepatic lipogenesis and inflammation. In conclusion, vitamin D and bile acid sequestration may be explored as new strategies to treat or prevent NASH.

Vitamin D deficiency impairs glucose-stimulated insulin secretion and increases insulin resistance by reducing PPAR-γ expression in nonobese Type 2 diabetic rats

“…ACCEPTED MANUSCRIPT 22 enterohepatic circulation of fat [47][48][49]. However, excessive vitamin D (220-270 IU/day/rat) did not reduce hepatic fat accumulation in the present study.…”

“…In the present study, PPAR-γ expression in the epidydimal fat pads was increased in the VD-normal and VD-high groups of the GK rats compared to the VD-low. Vitamin D deficiency is reported to increase non-alcoholic steatosis in humans and animals along with high fat diet and/or obesity [47][48][49]. In addition, vitamin D deficiency increased hepatic fat accumulation in GK rats fed a high fat diet, and suppressed expression of genes related to fatty acid oxidation and increased expression of lipogenic genes in the liver.…”

Vitamin D Signaling through Induction of Paneth Cell Defensins Maintains Gut Microbiota and Improves Metabolic Disorders and Hepatic Steatosis in Animal Models

“…In animal experiments, dietary vitamin D deficiency was found to exacerbate Toll-like receptor activation and hepatic inflammation in obese rats (Roth et al, 2012). In a mouse model, we previously demonstrated that vitamin D-deficient-high-fat diet (HFD+VDD) hampers the enterohepatic circulation of bile acids, leading to NASH (Kong et al, 2014). Furthermore, we recently found that long-term dietary vitamin D depletion could generate spontaneous liver fibrosis in a mice model (Zhu et al, 2015).…”

Effects of Gene Variants Controlling Vitamin D Metabolism and Serum Levels on Hepatic Steatosis

“…The role of vitamin D in the pathogenesis of fatty liver disease is being investigated in both preclinical [1, 2] and clinical studies [3, 4]. Epidemiological data indicate that vitamin D deficiency, as reflected by low serum ­concentrations of 25-hydroxyvitamin D (25(OH)D), is associated with an increased risk of nonalcoholic fatty liver disease (NAFLD) development [5, 6].…”

“…A recent meta-analysis found that NAFLD patients are more likely to present with vitamin D deficiency as compared to controls (odds ratio [OR] 1.26, 95% CI 1.17–1.35) [7]. In addition, Kong et al [1] showed that vitamin D supplementation is effective in preventing high-fat-diet-induced liver steatosis in rats. We observed this effect in humans, which resulted in modest yet significant improvements in controlled attenuation parameter (CAP) values, and hence a reduction in the degree of liver steatosis after only 4 weeks of vitamin D therapy [3].…”