A vitamin D receptor/SMAD genomic circuit gates hepatic fibrotic response.

Liver fibrosis is a reversible wound-healing response involving TGFß1/SMAD activation of hepatic stellate cells (HSCs). It results from excessive deposition of extracellular matrix components and can lead to impairment of liver function. Here, we show that vitamin D receptor (VDR) ligands inhibit HSC activation by TGFß1 and abrogate liver fibrosis, whereas Vdr knockout mice spontaneously develop hepatic fibrosis. Mechanistically, we show that TGFß1 signaling causes a redistribution of genome-wide VDR-binding sites (VDR cistrome) in HSCs and facilitates VDR binding at SMAD3 profibrotic target genes via TGFß1-dependent chromatin remodeling. In the presence of VDR ligands, VDR binding to the coregulated genes reduces SMAD3 occupancy at these sites, inhibiting fibrosis. These results reveal an intersecting VDR/SMAD genomic circuit that regulates hepatic fibrogenesis and define a role for VDR as an endocrine checkpoint to modulate the wound-healing response in liver. Furthermore, the findings suggest VDR ligands as a potential therapy for liver fibrosis.

Healthcare planning in north-east India: a survey on diabetes awareness, risk factors and health attitudes in a rural community.

AIMS AND OBJECTIVES: To determine the level of awareness and knowledge about diabetes in the community, to identify their risk factors for diabetes, the relationship between anthropometric measures and diabetes risk and estimate the burden of diabetes in this rural North-East Indian population with an objective to identify target areas for future healthcare planning. MATERIALS AND METHODS: A healthcare team conducted a community-based survey of the residents of Khowai district, Tripura. All household members above the age of 25 years were eligible to participate, following voluntary consent. Survey questionnaires were administered with interpreter assistance including demographic information, diabetes knowledge, family history, smoking, diet, healthcare access and the international physical activity questionnaire (IPAQ). Anthropometric measurements were taken and blood glucose testing performed. RESULTS: One hundred and forty four participants completed the survey, 66 males and 78 females with a mean age of 44.4 +/- 14.8 years Although 91% had heard about diabetes and 44% were concerned about developing it in the future, only 39% were aware of its association with overweight status and 37% knew it required long-term treatment. Nine percent were known to have pre-existing diabetes mellitus and a further 9% were newly detected to have diabetes mellitus or impaired glucose tolerance. Fifteen percent were hypertensive and 8% had a family history of diabetes. Their mean BMI was 21.2 kg/m2 and 31% were overweight, despite high levels of physical activity in 47%. For each predictor of increased risk--waist circumference (female >80 cm, male >94 cm), waist-height ratio >50% or BMI>23 kg/m2, subjects measuring above the cut-off were more likely to have abnormal glucose tolerance than those in the normal range (27% vs. 14.3% p = 0.08, 26.5% vs. 9.5% p = 0.008, 27.3% vs. 13.3% p = 0.043, respectively.) with waist-height ratio being the best predictor of an abnormal BGL: OR 3.45 CI (1.34 - 8.88). CONCLUSION: This is the first rural survey for diabetes in North-East India. This population had a low baseline knowledge and awareness about diabetes, despite significant diabetes prevalence. A greater emphasis on health education and risk factor modification for diabetes is warranted in the North-East part of the country.