Intestinal vitamin D receptor modulates lipid metabolism, adipose tissue inflammation and liver steatosis in obese mice

Jahn, Daniel; Dorbath, D; Schilling, A; Gildein, Lisa; Meier, Claus; Vuille‐dit‐Bille, Raphael N.; Schmitt, Johannes; Kraus, Daniel; Fleet, James C.; Hermanns, Heike M.; Geier, Andreas

doi:10.1016/j.bbadis.2019.03.007

Cited by 36 publications

(35 citation statements)

References 69 publications

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“…To the best of our knowledge, no data on VDR‐mediated ANGPTL3 gene regulation are available although this study has not been specifically designed for proving the causal nexus behind this observation. Besides, our findings are in line with previous studies that have shown that ANGPTL4 and ANGPTL8 are gene targets of VDR 12,13 . In these reports, VDR‐mediated gene regulation was shown to increase hepatic ANGPTL4 and ANGPTL8 expression and was associated with increased hepatic fat accumulation, 12,13 but ANGPTL3 expression was not evaluated.…”

Section: Discussionsupporting

confidence: 92%

“…Recent studies have demonstrated that ANGPTLs genes are targets of Vitamin D receptor (VDR), 12,13 a nuclear receptor regulating about 3% of the human genome 14 . Increased VDR signalling in hepatocytes was shown to promote ANGPTL8 expression, lipid synthesis and hepatosteatosis 12 ; likewise, gut ANGPTL4 expression is transcriptionally regulated by VDR and mediates intestine lipid absorption and intrahepatic fat accumulation 13 . VDRs are widely detectable in liver cells 15‐19 and initial evidence described novel pathways linking hepatic VDR expression to liver steatosis 20 .…”

Section: Introductionmentioning

confidence: 99%

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Relationship between hepatic and systemic angiopoietin‐like 3, hepatic Vitamin D receptor expression and NAFLD in obesity

Barchetta

Cimini

Chiappetta

et al. 2020

Liver International

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Background & Aims Non‐alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide and an independent risk factor for cardiovascular mortality. Angiopoietin‐like proteins (ANGPTLs) are targets for vitamin D receptor (VDR)‐mediated gene transcription and this axis may promote NAFLD. ANGPTL3 is a hepatokine which inhibits lipoprotein lipase and its experimentally induced inactivation reduces hepatosteatosis. Little is known on ANGPTL3 in human NAFLD and no data exist on its relationship with hepatic VDR/VD‐related genes. The aim of this research was to investigate hepatic ANGPTLs and VDR/VD‐related gene expression in human obesity in relation to NAFLD. Methods We conducted a cross‐sectional investigation on forty obese subjects with/without NAFLD. We evaluated hepatic ANGPTL3, ANGPTL4, ANGPTL8, LPL, VDR, CYP27A1 and CYP2R1 mRNA expression in liver biopsies by RT‐PCR; VDR expression was further investigated by immunohistochemistry; circulating ANGPTL3 was measured by Milliplex assay. Results Compared to non‐NAFLD, NAFLD individuals had significantly higher hepatic VDR, ANGPTL3 and LPL expression. ANGPTL3 correlated with steatosis grade, LPL, VDR, CYP27A1 and CYP2R1 expression. Plasma ANGPTL3 concentrations were positively associated with clinical/histological markers of NAFLD/NASH and with hepatic ANGPTL3 expression. Greater hepatic VDR expression was the main determinant of hepatic ANGPTL3 after adjusting for multiple confounders. Conclusions Hepatic ANGPTL3 expression correlates with greater VDR expression, presence and severity of NAFLD and translates in increased circulating ANGPTL3, likely as a result of its modulation by up‐regulated hepatic VDR in NAFLD. This study provides novel insights to potential mechanisms underlying ANGPTLs–mediated ectopic fat accumulation and NAFLD development in obesity.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Relationship between hepatic and systemic angiopoietin‐like 3, hepatic Vitamin D receptor expression and NAFLD in obesity

Barchetta

Cimini

Chiappetta

et al. 2020

Liver International

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“…The researchers found that vitamin D deficiency was seen in all races and in all age groups (8). Vitamin D deficiency is more common in obese people or obesity-related diseases, such as diabetes, so vitamin D supplements may also be a potential treatment (9). Vitamin D levels are not currently a concern for healthy people.…”

Section: Introductionmentioning

confidence: 99%

Correlation Between Hashimoto's Thyroiditis–Related Thyroid Hormone Levels and 25-Hydroxyvitamin D

2020

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The purpose of this study was to further clarify the association of Hashimoto's thyroiditis (HT) and vitamin D deficiency, and to seek the connection between them and related influencing factors. Methods: Data were obtained from subjects who underwent health examinations from January 2018 to December 2018. The diagnosis of HT was based on: antithyroid peroxidase antibody (TPO-Ab) levels >35 IU/ml and/or antithyroglobulin antibody (Tg-Ab) levels >40 IU/ml. Based on the Endocrine Society guidelines, 25-hydroxyvitamin D [25(OH)D] levels ≥30.0 ng/ml were classified as a vitamin D sufficiency; those between 20 and 29.9 ng/ml, as an insufficiency; and those <20 ng/ml, as a deficiency. All statistical analysis was performed by software R. Results: Of a total of 75,436 individuals who were physically examined, 5,656 of them had 25(OH)D levels tested at the same time; 5,230 were enrolled. The level of 25(OH)D in the non-HT group was higher than that in the HT group. Multiple regression analysis showed that HT was statistically significantly correlated with being male, body mass index (BMI), waist circumference, and thyroid-stimulating hormone (TSH). TSH levels in the insufficiency group and deficiency group were higher than those in the sufficiency group. Free triiodothyronine (FT3) and thyroxine (FT4) levels in the insufficiency group and deficiency group were lower than those in the sufficiency group. 25(OH)D increased by 1 ng/ml at the normal reference level, with an increase of 2.78 ng/dl in FT4 concentration and a decrease of 0.17 mIU/L in TSH. Conclusions: Patients with HT present with a reduced 25(OH)D level, and TSH is an independent risk factor for HT. TSH is negatively correlated with 25(OH)D level. FT3 and FT4 levels were positively correlated with 25(OH)D levels.

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“…Therefore, this study aimed to investigate ANGPTL4 and LPL expression in visceral AT (VAT) in relation to (i) local inflammation and dysfunction and (ii) clinical alterations, in human obesity. Moreover, since the vitamin D receptor (VDR) is involved in adipogenesis [ 20 ] and lipid accumulation in both liver [ 21 ] and AT [ 22 ] and a recent study demonstrated that VDR regulates ANGPTL4 gene expression in mice [ 23 ], we also explored VAT VDR expression in relation to local ANGPTL4 and LPL levels and the influence on the overall metabolic phenotype.…”

Section: Introductionmentioning

confidence: 99%

Angiopoietin-Like Protein 4 Overexpression in Visceral Adipose Tissue from Obese Subjects with Impaired Glucose Metabolism and Relationship with Lipoprotein Lipase

Barchetta

Chiappetta²,

Ceccarelli

et al. 2020

IJMS

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Angiopoietin-like protein 4 (ANGPTL4) regulates lipid partitioning by inhibiting circulating and tissue lipoprotein lipase (LPL); ANGPTL4 loss-of-function variants improve insulin sensitivity and reduce type 2 diabetes (T2D) risk with mechanisms partially unknown. This study was designed to explore metabolic implications of differential ANGPTL4 and LPL expression in human adipose tissue (AT). We recruited eighty-eight obese individuals, with and without abnormal glucose metabolism (AGM), undergoing bariatric surgery; visceral AT (VAT) fragments were obtained intra-operatively and analyzed by immunohistochemistry and mRNA by rt-PCR. Data on hepatic ANGPTL4 mRNA were available for 40 participants. VAT ANGPTL4 expression was higher in AGM individuals than in those with normal glucose tolerance (NGT) and associated with VAT inflammation, insulin resistance, and presence of adipocyte size heterogeneity. Increased ANGPTL4 was associated with AGM with OR = 5.1 (95% C.I.: 1.2–23; p = 0.02) and AUROC = 0.76 (95% C.I.: 1.2–23; p < 0.001). High LPL was associated with the detection of homogeneous adipocyte size, reduced microvessel density, and higher HIF-1α levels and inversely correlated to blood transaminases. In conclusion, in obese individuals, VAT ANGPTL4 levels are increased in the presence of local inflammation and AGM. Conversely, higher LPL expression describes a condition of increased lipid storage in adipocytes, which may serve as a protective mechanism against ectopic fat accumulation and related metabolic disease in obesity.

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Intestinal vitamin D receptor modulates lipid metabolism, adipose tissue inflammation and liver steatosis in obese mice

Cited by 36 publications

References 69 publications

Relationship between hepatic and systemic angiopoietin‐like 3, hepatic Vitamin D receptor expression and NAFLD in obesity

Relationship between hepatic and systemic angiopoietin‐like 3, hepatic Vitamin D receptor expression and NAFLD in obesity

Correlation Between Hashimoto's Thyroiditis–Related Thyroid Hormone Levels and 25-Hydroxyvitamin D

Angiopoietin-Like Protein 4 Overexpression in Visceral Adipose Tissue from Obese Subjects with Impaired Glucose Metabolism and Relationship with Lipoprotein Lipase

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