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.

• Authors: Ming Kong, Longdong Zhu, Li Bai, Xiaohui Zhang, Yu Chen, Shuang Liu, Sujun Zheng, Stephen J Pandol, Yuan-Ping Han, Zhongping Duan
• Journal: American journal of physiology. Gastrointestinal and liver physiology (Am J Physiol Gastrointest Liver Physiol) Vol. 307 Issue 9 Pg. G883-93 (Nov 01 2014) ISSN: 1522-1547 [Electronic] United States
• PMID: 25214402 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 the American Physiological Society.

Chemical References

• Bile Acids and Salts
• Organic Anion Transporters, Sodium-Dependent
• Srebf1 protein, mouse
• Sterol Regulatory Element Binding Protein 1
• Symporters
• fibroblast growth factor 15, mouse
• sodium-bile acid cotransporter
• Fibroblast Growth Factors
• Fatty Acid Synthases
• Calcitriol

Topics

• Animals
• Bile Acids and Salts (metabolism)
• Calcitriol (therapeutic use)
• Diet, High-Fat (adverse effects)
• Fatty Acid Synthases (genetics, metabolism)
• Fibroblast Growth Factors (genetics, metabolism)
• Ileum (metabolism, pathology)
• Lipogenesis
• Liver (metabolism, pathology)
• Male
• Mice
• Mice, Inbred BALB C
• Non-alcoholic Fatty Liver Disease (drug therapy, etiology, metabolism)
• Organic Anion Transporters, Sodium-Dependent (genetics, metabolism)
• Sterol Regulatory Element Binding Protein 1 (genetics, metabolism)
• Symporters (genetics, metabolism)
• Vitamin D Deficiency (complications, metabolism)