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Zhao Y, Fan J, Wang J, Wan J, Ma H, Sha X, Wang H. 1α,25(OH)2D3 Regulates the TGF-β1/Samd Signaling Pathway Inhibition of Hepatic Stellate Cell Activation. Drug Res (Stuttg) 2025; 75:94-99. [PMID: 39814037 DOI: 10.1055/a-2463-5530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2025]
Abstract
To investigate the effect of 1α,25(OH)2D3 on hepatic stellate cells and the mechanism of the TGF-β1/Smad signaling pathway.LX2 cells were treated with TGF-β1 and different concentrations of 1α,25(OH)2D3. Cell proliferation was assessed using the CCK8 assay to determine the optimal concentration of 1α,25(OH)2D3 activity. The cell cycle and apoptotic rates were evaluated using flow cytometry. The expressions of Samd2, Samd3, Samd4, and Samd7 was assessed by western blotting, whereas the expression of MMP1, MMP13, and TIMP-1 was detected by qPCR.Compared with the control group, the 1α,25(OH)2D3 group had a higher apoptotic rate of LX2 cells, the cell cycle was blocked from the G1 stage to the S stage, the expressions of Samd2, Samd7, MMP1, and MMP13 increased, while the expressions of Samd3, Samd4, and TIMP-1 decreased.1α,25(OH)2D3 inhibits hepatic stellate cell activation and exerts anti-hepatic fibrosis effects by downregulating the expression of Samd3, Samd4, TIMP-1 and upregulating the expression of Samd2, Samd4, MMP1, and MMP13.
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Affiliation(s)
- Yihan Zhao
- Xi'an Eighth Hospital, Xi'an, China
- Second Clinical College, Shaanxi University of Traditional Chinese Medicine, Xianyang, China
| | | | - Jia Wang
- Xi'an Eighth Hospital, Xi'an, China
| | - Jie Wan
- Xi'an Eighth Hospital, Xi'an, China
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Liu M, Song XZ, Yang L, Fang YH, Lan L, Cui JS, Lu XC, Zhu HY, Quan LH, Han HM. 1,25-dihydroxyvitamin D3 improves non-alcoholic steatohepatitis phenotype in a diet-induced rat model. Front Endocrinol (Lausanne) 2025; 16:1528768. [PMID: 40190400 PMCID: PMC11968344 DOI: 10.3389/fendo.2025.1528768] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Accepted: 02/18/2025] [Indexed: 04/09/2025] Open
Abstract
We studied the potential protective effects of 1,25-dihydroxyvitamin D3 (1,25 VD3) supplementation on liver damage induced by a choline-deficient (CD) diet in rats, where impaired liver function leads to decreased 25-hydroxyvitamin D3 levels, the precursor for the active 1,25 VD3. The CD diet reduced serum 25 VD3 levels and increased liver enzymes, indicative of liver damage. Conversely, 1,25 VD3 supplementation alleviated liver damage, reducing liver enzymes and improving histopathological features characteristic of non-alcoholic steatohepatitis (NASH). Oxidative stress and inflammation were mitigated by 1,25 VD3, as evidenced by decreased malondialdehyde and nuclear factor kappa B (NF-κB) expression, and increased total antioxidant capacity (TAOC). 1,25 VD3 also enhanced fatty acid metabolism by increasing peroxisome proliferator-activated receptor alpha (PPARα) and carnitine palmitoyltransferase-1 (CPT-1) expression, promoting lipid transport and oxidation. Additionally, 1,25 VD3 supplementation modulated inflammation by increasing PPARγ expression, reducing NF-κB expression, and decreasing pro-inflammatory cytokines (TNF-α, IL-1β). Anti-inflammatory cytokines (IL-10, IL-4) were increased, and macrophage polarization was shifted towards an anti-inflammatory M2 phenotype. Moreover, 1,25 VD3 upregulated CYP2J3, a cytochrome P450 epoxygenase that converts arachidonic acid to anti-inflammatory epoxyeicosatrienoic acids (EETs) and decreased soluble epoxide hydrolase activity, likely contributing to increased EET levels. Correlation studies revealed positive associations between 1,25 VD3 supplementation, CYP2J3 expression, EETs, as well as negative correlations with NF-κB and TNF-α. PPARα expression positively correlated with TAOC and CPT-1, while PPARγ expression negatively correlated with inflammatory markers. These findings demonstrate the therapeutic potential of 1,25 VD3 in alleviating NASH through regulation of fatty acid metabolism, inflammation, and oxidative stress.
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Affiliation(s)
- Mei Liu
- Department of Gastroenterology, Affiliated Hospital of Yanbian University, Yanji, Jilin, China
| | - Xiang-Zhun Song
- Department of Gastroenterology, Jilin Provincial People’s Hospital, Changchun, Jilin, China
| | - Liu Yang
- Department of Gastroenterology and Hepatology, Characteristic Medical Center of the Chinese People’s Armed Police Force, Tianjin Key Laboratory of Hepatopancreatic Fibrosis and Molecular Diagnosis & Treatment, Tianjin, China
| | - Yu-Hui Fang
- Department of Dermatology, Fuyang People’s Hospital of Anhui Medical University, Fuyang, Anhui, China
| | - Liu Lan
- Department of Pathology, Affiliated Hospital of Yanbian University, Yanji, Jilin, China
| | - Jing-Shu Cui
- Department of Pathology, Affiliated Hospital of Yanbian University, Yanji, Jilin, China
| | - Xiao-Chen Lu
- Department of Gastroenterology, Jimo District People’s Hospital, Qingdao, Shandong, China
| | - Hai-Yang Zhu
- Department of Gastroenterology, Affiliated Hospital of Yanbian University, Yanji, Jilin, China
| | - Lin-Hu Quan
- Department of College of Pharmacy, Yanbian University, Yanji, Jilin, China
| | - Hong-Mei Han
- Department of Gastroenterology, Affiliated Hospital of Yanbian University, Yanji, Jilin, China
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Abbasi M, Heath B, McGinness L. Effects of Multivitamin Supplementation on Metabolic Parameters in High- and Low-Fat Diet-Fed C57BL/6J Mice: Potential Links to Adipose Tissue Browning and Gut Microbiome. Nutrients 2025; 17:1045. [PMID: 40292481 PMCID: PMC11944532 DOI: 10.3390/nu17061045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2025] [Revised: 03/09/2025] [Accepted: 03/12/2025] [Indexed: 04/30/2025] Open
Abstract
BACKGROUND/OBJECTIVES The relationship between diet, micronutrient supplementation, and metabolic regulation emphasizes the potential of nutritional strategies to address obesity and related disorders. Certain vitamins have the potential to enhance thermogenesis and metabolic health. However, the impact of multivitamin supplementation on white adipose tissue (WAT) browning, the gut microbiome (GM), and metabolic function is not well understood. This study investigated the effects of multivitamin supplementation on obesity-related metabolic dysfunction in mice fed a high-fat diet (HFD) or a low-fat diet (LFD). METHODS Male C57BL/6J mice were assigned to group 1: control chow diet (CHD); 2: control HFD; 3: multivitamin-supplemented HFD (Mv-HFD); 4: control LFD; or 5: multivitamin-supplemented LFD (Mv-LFD). Diets, either supplemented with multivitamins A, D, B1, B5, and C or non-supplemented, were administered for 12 weeks. Metabolic parameters, adipose tissue browning, and the GM composition were analyzed. RESULTS The Mv-HFD significantly reduced weight gain, adipose tissue mass, blood glucose levels, and insulin resistance induced by an HFD. Additionally, it increased energy expenditure and thermogenic gene expression in WAT. Both the Mv-HFD and Mv-LFD improved the GM composition by increasing beneficial bacteria. CONCLUSIONS Multivitamin supplementation improved metabolic health by potentially promoting WAT browning, enhancing energy expenditure, and modulating the GM composition. These findings suggest that multivitamins could offer a promising strategy for combating obesity and associated metabolic dysfunction.
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Affiliation(s)
- Mehrnaz Abbasi
- Department of Nutritional Sciences, College of Human Sciences, Auburn University, Auburn, AL 36849, USA
| | - Braeden Heath
- Department of Biomedical Sciences, College of Sciences and Mathematics, Auburn University, Auburn, AL 36849, USA
| | - Lauren McGinness
- Department of Nutritional Sciences, College of Human Sciences, Auburn University, Auburn, AL 36849, USA
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Li J, Yan N, Li X, He S. Association between serum vitamin D concentration and liver fibrosis in diabetes mellitus patients: a cross-sectional study from the NHANES database. Acta Diabetol 2024; 61:1393-1402. [PMID: 38831202 DOI: 10.1007/s00592-024-02292-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Accepted: 04/14/2024] [Indexed: 06/05/2024]
Abstract
AIM Liver fibrosis (LF) is a common complication of diabetes mellitus (DM). Studies have found that vitamin D (VD), as a modifiable factor has been reported to be associated with LF. The relationship between serum VD concentration and LF in DM patients has rarely been reported. The aim of this study was to assess the association between serum VD concentration and LF in DM patients. METHODS In this cross-sectional study, data of DM patients aged ≥ 45 years were extracted from the National Health and Nutrition Examination Survey (NHANES 2017-2018). Serum VD concentration was measured by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Vibration controlled transient elastography (VCTE) was used to measure liver stiffness. Covariates included sociodemographic information, lifestyles, laboratory data, diseases history were extracted from the database. The weighted univariable and multivariable logistic regression models were utilized to explore the association between serum VD concentration and LF in DM patients, and were described as odds ratio (ORs) and 95% confidence intervals (CIs). Subgroup analyses based on BMI, liver steatosis, hypertension and dyslipidemia were further assessed the association. RESULTS A total of 799 patients were included, of which 188 (23.53%) had LF. Higher serum VD concentration was associated with the lower odds of LF (OR = 0.33, 95% CI 0.19-0.59) and advanced LF (OR = 0.31, 95% CI 0.17-0.55) in DM patients after adjustment for race, liver steatosis, BMI, smoking, drinking, AST, ALT and physical activity, especially in patients with liver steatosis (OR = 0.28, 95% CI 0.13-0.59) and dyslipidemia (OR = 0.31, 95% CI 0.14-0.66), respectively. CONCLUSIONS High serum VD concentration may have a potential benefit for maintain the liver health in DM patients.
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Affiliation(s)
- Jing Li
- Department of Endocrinology Diabetes, Shaanxi Provincial People's Hospital, No. 256 Youyi West Road, Beilin District, Xi'an, 710068, China
| | - Ni Yan
- Department of Endocrinology Diabetes, Shaanxi Provincial People's Hospital, No. 256 Youyi West Road, Beilin District, Xi'an, 710068, China
| | - Xiaofeng Li
- Department of Endocrinology Diabetes, Shaanxi Provincial People's Hospital, No. 256 Youyi West Road, Beilin District, Xi'an, 710068, China
| | - Shenglin He
- Department of Endocrinology Diabetes, Shaanxi Provincial People's Hospital, No. 256 Youyi West Road, Beilin District, Xi'an, 710068, China.
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Zhang Y, Zhang M, Jiang S, Hu H, Wang X, Yu F, Huang Y, Liang Y. Associations of perfluoroalkyl substances with metabolic-associated fatty liver disease and non-alcoholic fatty liver disease: NHANES 2017-2018. Cancer Causes Control 2024; 35:1271-1282. [PMID: 38764062 DOI: 10.1007/s10552-024-01865-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 02/14/2024] [Indexed: 05/21/2024]
Abstract
OBJECTIVES This study investigated the potential effects of perfluoroalkyl substance (PFAS) in serum on MAFLD, NAFLD, and liver fibrosis. METHODS Our sample included 696 participants (≥ 18 years) from the 2017-2018 NHANES study with available serum PFASs, covariates, and outcomes. Using the first quartile of PFAS as the reference group, we used weighted binary logistic regression and multiple ordered logistic regression used to analyze the relationship between PFAS and MAFLD, NAFLD, and liver fibrosis and multiple ordinal logistic regression to investigate the relationship between PFAS and MAFLD, NAFLD, and liver fibrosis and calculated the odds ratio (OR) and 95% confidence interval for each chemical. Finally, stratified analysis and sensitivity analysis were performed according to gender, age, BMI, and serum cotinine concentration. RESULTS A total of 696 study subjects were included, including 212 NAFLD patients (weighted 27.03%) and 253 MAFLD patients (weighted 32.65%). The quartile 2 of serum PFOA was positively correlated with MAFLD and NAFLD (MAFLD, OR 2.29, 95% CI 1.05-4.98; NAFLD, OR 2.37, 95% CI 1.03-5.47). PFAS were not significantly associated with liver fibrosis after adjusting for potential confounders in MAFLD and NAFLD. Stratified analysis showed that PFOA was strongly associated with MAFLD, NAFLD, and liver fibrosis in males and obese subjects. In women over 60 years old, PFHxS was also correlated with MAFLD, NAFLD, and liver fibrosis. CONCLUSION The serum PFOA was positively associated with MAFLD and NAFLD in US adults. After stratified analysis, the serum PFHxS was correlated with MFALD, NAFLD, and liver fibrosis.
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Affiliation(s)
- Yuxiao Zhang
- School of Public Health, Wannan Medical College, 22 Wenchang West Road, Wuhu, 241000, Anhui, China
| | - Min Zhang
- School of Public Health, Wannan Medical College, 22 Wenchang West Road, Wuhu, 241000, Anhui, China
| | - Shanjiamei Jiang
- School of Public Health, Wannan Medical College, 22 Wenchang West Road, Wuhu, 241000, Anhui, China
| | - Heng Hu
- Department of Otolaryngology Head and Neck Surgery, The First Affiliated Hospital of Wannan Medical College, Wuhu, 241001, Anhui, China
| | - Xinzhi Wang
- School of Public Health, Wannan Medical College, 22 Wenchang West Road, Wuhu, 241000, Anhui, China
| | - Fan Yu
- School of Public Health, Wannan Medical College, 22 Wenchang West Road, Wuhu, 241000, Anhui, China
| | - Yue'e Huang
- School of Public Health, Wannan Medical College, 22 Wenchang West Road, Wuhu, 241000, Anhui, China.
| | - Yali Liang
- School of Public Health, Wannan Medical College, 22 Wenchang West Road, Wuhu, 241000, Anhui, China.
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Yang A, Chen Y, Gao Y, Lv Q, Li Y, Li F, Yu R, Han Z, Dai S, Zhu J, Yang C, Zhan S, Sun L, Zhou JC. Vitamin D 3 exacerbates steatosis while calcipotriol inhibits inflammation in non-alcoholic fatty liver disease in Sod1 knockout mice: a comparative study of two forms of vitamin D. Food Funct 2024; 15:4614-4626. [PMID: 38590249 DOI: 10.1039/d4fo00215f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/10/2024]
Abstract
The role of vitamin D (VD) in non-alcoholic fatty liver disease (NAFLD) remains controversial, possibly due to the differential effects of various forms of VD. In our study, Sod1 gene knockout (SKO) mice were utilized as lean NAFLD models, which were administered 15 000 IU VD3 per kg diet, or intraperitoneally injected with the active VD analog calcipotriol for 12 weeks. We found that VD3 exacerbated hepatic steatosis in SKO mice, with an increase in the levels of Cd36, Fatp2, Dgat2, and CEBPA. However, calcipotriol exerted no significant effect on hepatic steatosis. Calcipotriol inhibited the expression of Il-1a, Il-1b, Il-6, Adgre1, and TNF, with a reduction of NFκB phosphorylation in SKO mice. No effect was observed by either VD3 or calcipotriol on hepatocyte injury and hepatic fibrosis. Co-immunofluorescence stains of CD68, a liver macrophage marker, and VDR showed that calcipotriol reduced CD68 positive cells, and increased the colocalization of VDR with CD68. However, VD3 elevated hepatocyte VDR expression, with no substantial effect on the colocalization of VDR with CD68. Finally, we found that VD3 increased the levels of serum 25(OH)D3 and 24,25(OH)2D3, whereas calcipotriol decreased both. Both VD3 and calcipotriol did not disturb serum calcium and phosphate levels. In summary, our study found that VD3 accentuated hepatic steatosis, while calcipotriol diminished inflammation levels in SKO mice, and the difference might stem from their distinct cellular selectivity in activating VDR. This study provides a reference for the application of VD in the treatment of lean NAFLD.
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Affiliation(s)
- Aolin Yang
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, Guangdong, China.
| | - Yanmei Chen
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, Guangdong, China.
- Guangzhou Center for Disease Control and Prevention, Guangzhou, Guangdong 510440, China
| | - Yizhen Gao
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, Guangdong, China.
| | - Qingqing Lv
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, Guangdong, China.
| | - Yao Li
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, Guangdong, China.
| | - Fengna Li
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, Guangdong, China.
| | - Ruirui Yu
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, Guangdong, China.
| | - Ziyu Han
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, Guangdong, China.
| | - Shimiao Dai
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, Guangdong, China.
| | - Junying Zhu
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, Guangdong, China.
| | - Chenggang Yang
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, Guangdong, China.
| | - Shi Zhan
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, Guangdong, China.
| | - Litao Sun
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, Guangdong, China.
| | - Ji-Chang Zhou
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, Guangdong, China.
- Guangdong Province Engineering Laboratory for Nutrition Translation, Shenzhen 518107, Guangdong, China
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangzhou 510080, Guangdong, China
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Ramalingam L, Mabry B, Menikdiwela KR, Moussa H, Moustaid-Moussa N. Enhanced Metabolic Effects of Fish Oil When Combined with Vitamin D in Diet-Induced Obese Male Mice. Biomolecules 2024; 14:474. [PMID: 38672490 PMCID: PMC11048485 DOI: 10.3390/biom14040474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 03/30/2024] [Accepted: 04/09/2024] [Indexed: 04/28/2024] Open
Abstract
Vitamin D (vit D) and fish oil (FO) both offer unique health benefits, however, their combined effects have not been evaluated in obesity and nonalcoholic fatty liver disease (NAFLD). Hence, we hypothesized that vit D and FO supplementation would have additive effects in reducing obesity-associated inflammation and NAFLD. Male C57BL6 mice were split into four groups and fed a high fat (HF) diet supplemented with a low (HF; +200 IU vit D) or high dose of vitamin D (HF + D; +1000 IU vit D); combination of vit D and FO (HF-FO; +1000 IU vit D); or only FO (HF-FO; +200 IU vit D) for 12 weeks. We measured body weight, food intake, glucose tolerance, and harvested epididymal fat pad and liver for gene expression analyses. Adiposity was reduced in groups supplemented with both FO and vit D. Glucose clearance was higher in FO-supplemented groups compared to mice fed HF. In adipose tissue, markers of fatty acid synthesis and oxidation were comparable in groups that received vit D and FO individually in comparison to HF. However, the vit D and FO group had significantly lower fatty acid synthesis and higher oxidation compared to the other groups. Vit D and FO also significantly improved fatty acid oxidation, despite similar fatty acid synthesis among the four groups in liver. Even though we did not find additive effects of vit D and FO, our data provide evidence that FO reduces markers of obesity in the presence of adequate levels of vit D.
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Affiliation(s)
- Latha Ramalingam
- Nutrigenomics, Inflammation and Obesity Research Laboratory, Department of Nutritional Sciences, Texas Tech University (TTU), Lubbock, TX 79409, USA (K.R.M.)
- Obesity Research Institute, Office of Research & Innovation, Texas Tech University (TTU), Lubbock, TX 79409, USA
| | - Brennan Mabry
- Nutrigenomics, Inflammation and Obesity Research Laboratory, Department of Nutritional Sciences, Texas Tech University (TTU), Lubbock, TX 79409, USA (K.R.M.)
| | - Kalhara R. Menikdiwela
- Nutrigenomics, Inflammation and Obesity Research Laboratory, Department of Nutritional Sciences, Texas Tech University (TTU), Lubbock, TX 79409, USA (K.R.M.)
- Obesity Research Institute, Office of Research & Innovation, Texas Tech University (TTU), Lubbock, TX 79409, USA
| | - Hanna Moussa
- Obesity Research Institute, Office of Research & Innovation, Texas Tech University (TTU), Lubbock, TX 79409, USA
- Department of Physics & Astronomy, College of Arts & Sciences, Texas Tech University (TTU), Lubbock, TX 79409, USA
| | - Naima Moustaid-Moussa
- Nutrigenomics, Inflammation and Obesity Research Laboratory, Department of Nutritional Sciences, Texas Tech University (TTU), Lubbock, TX 79409, USA (K.R.M.)
- Obesity Research Institute, Office of Research & Innovation, Texas Tech University (TTU), Lubbock, TX 79409, USA
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Liu Y, Qin X, Chen T, Chen M, Wu L, He B. Exploring the interactions between metabolic dysfunction-associated fatty liver disease and micronutrients: from molecular mechanisms to clinical applications. Front Nutr 2024; 11:1344924. [PMID: 38549744 PMCID: PMC10973017 DOI: 10.3389/fnut.2024.1344924] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Accepted: 03/05/2024] [Indexed: 01/06/2025] Open
Abstract
Metabolic (dysfunction)-associated fatty liver disease (MAFLD) has emerged as a significant global health concern, representing a major cause of liver disease worldwide. This condition spans a spectrum of histopathologic stages, beginning with simple fatty liver (MAFL), characterized by over 5% fat accumulation, and advancing to metabolic (dysfunction)-associated steatohepatitis, potentially leading to hepatocellular carcinoma. Despite extensive research, there remains a substantial gap in effective therapeutic interventions. This condition's progression is closely tied to micronutrient levels, crucial for biological functions like antioxidant activities and immune efficiency. The levels of these micronutrients exhibit considerable variability among individuals with MAFLD. Moreover, the extent of deficiency in these nutrients can vary significantly throughout the different stages of MAFLD, with disease progression potentially exacerbating these deficiencies. This review focuses on the role of micronutrients, particularly vitamins A, D, E, and minerals like iron, copper, selenium, and zinc, in MAFLD's pathophysiology. It highlights how alterations in the homeostasis of these micronutrients are intricately linked to the pathophysiological processes of MAFLD. Concurrently, this review endeavors to harness the existing evidence to propose novel therapeutic strategies targeting these vitamins and minerals in MAFLD management and offers new insights into disease mechanisms and treatment opportunities in MAFLD.
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Affiliation(s)
- Yuan Liu
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China
| | - Xiang Qin
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China
| | - Tianzhu Chen
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China
| | - Mengyao Chen
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China
| | - Liyan Wu
- Department of Gastroenterology, Tongde Hospital of Zhejiang Province, Hangzhou, China
| | - Beihui He
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China
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Atteia HH. MicroRNAs in Anticancer Drugs Hepatotoxicity: From Pathogenic Mechanism and Early Diagnosis to Therapeutic Targeting by Natural Products. Curr Pharm Biotechnol 2024; 25:1791-1806. [PMID: 38178678 DOI: 10.2174/0113892010282155231222071903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 11/11/2023] [Accepted: 11/24/2023] [Indexed: 01/06/2024]
Abstract
Patients receiving cancer therapies experience severe adverse effects, including hepatotoxicity, even at therapeutic doses. Consequently, monitoring patients on cancer therapy for hepatic functioning is necessary to avoid permanent liver damage. Several pathways of anticancer drug-induced hepatotoxicity involve microRNAs (miRNAs) via targeting mRNAs. These short and non-coding RNAs undergo rapid modulation in non-targeted organs due to cancer therapy insults. Recently, there has been an interest for miRNAs as useful and promising biomarkers for monitoring toxicity since they have conserved sequences across species and are cellular-specific, stable, released during injury, and simple to analyze. Herein, we tried to review the literature handling miRNAs as mediators and biomarkers of anticancer drug-induced hepatotoxicity. Natural products and phytochemicals are suggested as safe and effective candidates in treating cancer. There is also an attempt to combine anticancer drugs with natural compounds to enhance their efficiencies and reduce systemic toxicities. We also discussed natural products protecting against chemotherapy hepatotoxicity via modulating miRNAs, given that miRNAs have pathogenic and diagnostic roles in chemotherapy-induced hepatotoxicity and that many natural products can potentially regulate their expression. Future studies should integrate these findings into clinical trials by formulating suitable therapeutic dosages of natural products to target miRNAs involved in anticancer drug hepatotoxicity.
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Affiliation(s)
- Hebatallah Husseini Atteia
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia
- Department of Biochemistry, Faculty of Pharmacy, Zagazig University, Zagazig, Sharkia, 44519, Egypt
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10
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Haroun N, Bennour I, Seipelt E, Astier J, Sani L, Tardivel C, Svilar L, Martin JC, Mounien L, Landrier JF. Maternal Vitamin D Deficiency in Mice Sex-Dependently Affects Hepatic Lipid Accumulation in Offspring. Mol Nutr Food Res 2024; 68:e2300290. [PMID: 38010607 DOI: 10.1002/mnfr.202300290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 10/18/2023] [Indexed: 11/29/2023]
Abstract
SCOPE Vitamin D deficiency (VDD) is becoming a global issue and low 25-hydroxyvitamin D (25(OH)D) plasma levels have been linked to hepatic steatosis in adulthood. Nevertheless, the impact of maternal VDD on lipid metabolism and hepatic steatosis remains poorly documented, especially under obesogenic condition. The goal of this study is to assess the effects of maternal VDD on hepatic lipid accumulation in adult offspring fed a normal or obesogenic diet. METHODS AND RESULTS Several approaches are implemented including histology and lipidomics on the liver in both males and females. No major impact of high-fat (HF) or VDD is observed at histological level in both males and females. Nevertheless, in males born from VDD mice and fed an HF diet, an increase of total lipids and modulation of the relative lipid species distribution characterized by a decrease of triglycerides and increase of phospholipids is observed. In female no major lipid profile is noticed. CONCLUSION Maternal VDD combined with a HF diet in male may predispose to hepatic hypertrophia, with a specific lipid profile. Such observations reinforce our knowledge of the impact of maternal VDD on hepatic programming in the offspring.
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Affiliation(s)
- Nicole Haroun
- Aix-Marseille Université, C2VN, INRAE, INSERM, Marseille, 13000, France
| | - Imene Bennour
- Aix-Marseille Université, C2VN, INRAE, INSERM, Marseille, 13000, France
| | - Eva Seipelt
- Aix-Marseille Université, C2VN, INRAE, INSERM, Marseille, 13000, France
| | - Julien Astier
- Aix-Marseille Université, C2VN, INRAE, INSERM, Marseille, 13000, France
| | - Léa Sani
- Aix-Marseille Université, C2VN, INRAE, INSERM, Marseille, 13000, France
| | - Catherine Tardivel
- Aix-Marseille Université, C2VN, INRAE, INSERM, Marseille, 13000, France
- Biomet, C2VN, CriBiom, Marseille, 13000, France
| | - Ljubica Svilar
- Aix-Marseille Université, C2VN, INRAE, INSERM, Marseille, 13000, France
- Biomet, C2VN, CriBiom, Marseille, 13000, France
| | - Jean-Charles Martin
- Aix-Marseille Université, C2VN, INRAE, INSERM, Marseille, 13000, France
- Biomet, C2VN, CriBiom, Marseille, 13000, France
| | - Lourdes Mounien
- Aix-Marseille Université, C2VN, INRAE, INSERM, Marseille, 13000, France
- PhenoMARS, C2VN, CriBiom, Marseille, 13000, France
| | - Jean François Landrier
- Aix-Marseille Université, C2VN, INRAE, INSERM, Marseille, 13000, France
- PhenoMARS, C2VN, CriBiom, Marseille, 13000, France
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11
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Kuwabara N, Sato S, Nakagawa S. Effects of Long-Term High-Ergosterol Intake on the Cholesterol and Vitamin D Biosynthetic Pathways of Rats Fed a High-Fat and High-Sucrose Diet. Biol Pharm Bull 2023; 46:1683-1691. [PMID: 37779053 DOI: 10.1248/bpb.b23-00348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/03/2023]
Abstract
Dyslipidemia is a lifestyle-related (physical inactivity or obesity) disease; therefore, dietary foods that can easily be consumed in daily life is important to prevent dyslipidemia. Ergosterol, a precursor of vitamin D2, is a fungal sterol present in the membranes of edible mushrooms and other fungi. Ergosterol is converted to brassicasterol by 7-dehydrocholesterol reductase (DHCR7), a cholesterol biosynthesis enzyme that converts 7-dehydrocholesterol (a precursor of vitamin D3) into cholesterol. Previously, we reported that ergosterol increases 7-dehydrocholesterol, decreases cholesterol levels by competitive effect of DHCR7, and reduces DHCR7 mRNA and protein levels in human HepG2 hepatoma cells. Here, we investigated the effects of long-term high ergosterol intake on the cholesterol, vitamin D2, and D3 biosynthetic pathways of rats fed a high-fat and high-sucrose (HFHS) diet using GC-MS and LC with tandem mass spectrometry. In HFHS rats, oral ergosterol administration for 14 weeks significantly decreased plasma low-density lipoprotein cholesterol, total bile acid, and cholesterol precursor (squalene and desmosterol) levels and increased 7-dehydrocholesterol levels compared to HFHS rats without ergosterol. Ergosterol, brassicasterol, and vitamin D2 were detected, cholesterol levels were slightly decreased, and levels of vitamin D3 and its metabolites were slightly increased in rats fed HFHS with ergosterol. These results showed that ergosterol increased vitamin D2 levels, inhibited the cholesterol biosynthetic pathway, and possibly promoted vitamin D3 biosynthesis in vivo. Therefore, daily ergosterol intake may aid in the prevention of dyslipidemia.
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Affiliation(s)
- Naoko Kuwabara
- Graduate School of Pharmaceutical Sciences, Niigata University of Pharmacy and Medical and Life Sciences
| | - Shinji Sato
- Laboratory of Functional and Analytical Food Sciences, Faculty of Applied Life Sciences, Niigata University of Pharmacy and Medical and Life Sciences
| | - Saori Nakagawa
- Graduate School of Pharmaceutical Sciences, Niigata University of Pharmacy and Medical and Life Sciences
- Division of Bio-Analytical Chemistry, Faculty of Medical Technology, Niigata University of Pharmacy and Medical and Life Sciences
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12
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Lu S, Cao ZB. Interplay between Vitamin D and Adipose Tissue: Implications for Adipogenesis and Adipose Tissue Function. Nutrients 2023; 15:4832. [PMID: 38004226 PMCID: PMC10675652 DOI: 10.3390/nu15224832] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 11/10/2023] [Accepted: 11/16/2023] [Indexed: 11/26/2023] Open
Abstract
Adipose tissue encompasses various types, including White Adipose Tissue (WAT), Brown Adipose Tissue (BAT), and beige adipose tissue, each having distinct roles in energy storage and thermogenesis. Vitamin D (VD), a fat-soluble vitamin, maintains a complex interplay with adipose tissue, exerting significant effects through its receptor (VDR) on the normal development and functioning of adipocytes. The VDR and associated metabolic enzymes are widely expressed in the adipocytes of both rodents and humans, and they partake in the regulation of fat metabolism and functionality through various pathways. These encompass adipocyte differentiation, adipogenesis, inflammatory responses, and adipokine synthesis and secretion. This review primarily appraises the role and mechanisms of VD in different adipocyte differentiation, lipid formation, and inflammatory responses, concentrating on the pivotal role of the VD/VDR pathway in adipogenesis. This insight furnishes new perspectives for the development of micronutrient-related intervention strategies in the prevention and treatment of obesity.
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Affiliation(s)
| | - Zhen-Bo Cao
- School of Exercise and Health, Shanghai University of Sport, Shanghai 200438, China;
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13
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Corbin KD, Pittas AG, Desouza C, Grdinovac KK, Herzig KH, Kashyap SR, Kim SH, Nelson J, Rasouli N, Vickery EM, Knowler WC, Pratley RE. Indices of hepatic steatosis and fibrosis in prediabetes and association with diabetes development in the vitamin D and type 2 diabetes study. J Diabetes Complications 2023; 37:108475. [PMID: 37104979 PMCID: PMC10683797 DOI: 10.1016/j.jdiacomp.2023.108475] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 04/07/2023] [Accepted: 04/11/2023] [Indexed: 04/29/2023]
Abstract
AIMS Non-alcoholic fatty liver disease (NAFLD) is a common comorbidity that leads to poor outcomes in people at high risk for development of type 2 diabetes (T2D). Vitamin D is a possible mediator. In the vitamin D and type 2 diabetes study (D2d), we investigated the relationship of baseline indices of NAFLD with incident T2D and whether the effect of vitamin D on diabetes was modified by NAFLD. METHODS Cross-sectional associations of indices of NAFLD with glycemia and vitamin D status were assessed in 3972 individuals screened for the D2d study. In those with prediabetes randomized to vitamin D or placebo (n = 2423), we examined longitudinal associations of NAFLD indices with incident T2D. We used validated non-invasive scores to assess steatosis [(hepatic steatosis index (HSI); NAFLD-liver fat score (NAFLD-LFS)] and advanced fibrosis [fibrosis-4 (FIB-4) index; AST to Platelet Ratio Index (APRI)]. RESULTS Eighty-five percent of screened participants had likely steatosis by HSI and 71 % by NAFLD-LFS; 3 % were likely to have advanced fibrosis by FIB-4 and 1.2 % by APRI. FIB-4 indicated that 20.4 % of individuals require further follow up to assess liver health. Steatosis and fibrosis scores were higher among participants with worse glycemia. The NAFLD-LFS and APRI predicted development of diabetes (hazard ratios [95%CI] 1.35 [1.07, 1.70]; P = 0.012) and 2.36 (1.23, 4.54; P = 0.010), respectively). The effect of vitamin D on diabetes risk was not modified by baseline NAFLD indices. Individuals with likely steatosis had a smaller increase in serum 25-hydroxyvitamin D level in response to vitamin D than those without steatosis. CONCLUSIONS The predicted high prevalence of steatosis, the need for further fibrosis workup, and the relationship between liver health and incident T2D suggest that routine screening with clinically accessible scores may be an important strategy to reduce disease burden.
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Affiliation(s)
- Karen D Corbin
- AdventHealth Translational Research Institute, Orlando, FL, United States of America.
| | | | - Cyrus Desouza
- The University of Nebraska Medical Center and Omaha Veterans Affairs Medical Center, Omaha, NE, United States of America
| | | | - Karl-Heinz Herzig
- Research Unit of Biomedicine and Internal Medicine, Faculty of Medicine, and Medical Research Center, University of Oulu and Oulu University Hospital, 90220 Oulu, Finland; Department of Pediatric Gastroenterology and Metabolic Diseases, Pediatric Institute, Poznan University of Medical Sciences, 60-572 Poznań, Poland
| | | | - Sun H Kim
- Stanford University Medical Center, Stanford, CA, United States of America
| | - Jason Nelson
- Tufts Medical Center, Boston, MA, United States of America
| | - Neda Rasouli
- The University of Colorado School of Medicine, Aurora, CO, United States of America; The Veterans Affairs Eastern Colorado Health Care System, Aurora, CO, United States of America
| | | | - William C Knowler
- National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, AZ, United States of America
| | - Richard E Pratley
- AdventHealth Translational Research Institute, Orlando, FL, United States of America.
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14
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Sriphoosanaphan S, Rattanachaisit P, Somanawat K, Wanpiyarat N, Komolmit P, Werawatganon D. Calcitriol Protects against Acetaminophen-Induced Hepatotoxicity in Mice. Biomedicines 2023; 11:1534. [PMID: 37371630 DOI: 10.3390/biomedicines11061534] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 05/22/2023] [Accepted: 05/24/2023] [Indexed: 06/29/2023] Open
Abstract
Acetaminophen (APAP) overdose is one of the major causes of acute liver failure. Severe liver inflammation and the production of oxidative stress occur due to toxic APAP metabolites and glutathione depletion. Growing evidence has proved that vitamin D (VD) exerts anti-inflammatory and antioxidative functions. Our objective was to explore the protective role of calcitriol (VD3) in acute APAP-induced liver injury. Methods: Adult male mice were randomized into three groups; control (n = 8), APAP (n = 8), and VD3 group (n = 8). All mice, except controls, received oral administration of APAP (400 mg/kg) and were sacrificed 24 h later. In the VD3 group, calcitriol (10 µg/kg) was injected intraperitoneally 24 h before and after exposure to APAP. Blood samples were collected to assess serum aminotransferase and inflammatory cytokines [tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6)]. Liver tissues were analyzed for hepatic glutathione (GSH), malondialdehyde (MDA), and histopathology. Results: APAP administration significantly increased serum aminotransferase, inflammatory cytokines, and induced cellular inflammation and necrosis. APAP also depleted hepatic GSH and elevated oxidative stress, as indicated by high MDA levels. In the APAP group, 25% of the mice (two out of eight) died, while no deaths occurred in the VD3 group. Treatment with calcitriol significantly reduced serum aminotransferase, TNF-α, and IL-6 levels in the VD3 group compared to the APAP group. Additionally, VD3 effectively restored GSH reserves, reduced lipid peroxidation, and attenuated hepatotoxicity. Conclusions: These findings demonstrate that VD3 prevents APAP-induced acute liver injury and reduces mortality in mice through its anti-inflammatory and antioxidative activity. Thus, VD3 might be a novel treatment strategy for APAP-induced hepatotoxicity.
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Affiliation(s)
- Supachaya Sriphoosanaphan
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Bangkok 10330, Thailand
- Center of Excellence in Liver Diseases, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok 10330, Thailand
| | - Pakkapon Rattanachaisit
- Center of Excellence in Alternative and Complementary Medicine for Gastrointestinal and Liver Diseases, Department of Physiology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
| | - Kanjana Somanawat
- Center of Excellence in Alternative and Complementary Medicine for Gastrointestinal and Liver Diseases, Department of Physiology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
| | - Natcha Wanpiyarat
- Department of Pathology, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Bangkok 10330, Thailand
| | - Piyawat Komolmit
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Bangkok 10330, Thailand
- Center of Excellence in Liver Diseases, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok 10330, Thailand
| | - Duangporn Werawatganon
- Center of Excellence in Alternative and Complementary Medicine for Gastrointestinal and Liver Diseases, Department of Physiology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
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15
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Chen Q, Zhao L, Mei L, Zhao X, Han P, Liu J, Meng C, Li R, Zhong R, Wang K, Li J. Vitamin C and vitamin D3 alleviate metabolic-associated fatty liver disease by regulating the gut microbiota and bile acid metabolism via the gut-liver axis. Front Pharmacol 2023; 14:1163694. [PMID: 37089915 PMCID: PMC10113476 DOI: 10.3389/fphar.2023.1163694] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Accepted: 03/27/2023] [Indexed: 04/09/2023] Open
Abstract
Background: Previous studies have demonstrated that both vitamin C (VC) and vitamin D3 (VD3) have therapeutic potential against metabolic disorders, including obesity, diabetes, and metabolic-associated fatty liver disease (MAFLD). However, it is unclear whether VC supplementation is associated with improving the intestinal flora and regulating the metabolism of bile acids via the gut-liver axis in MAFLD. There is still no direct comparison or combination study of these two vitamins on these effects.Methods: In this study, we employed biochemical, histological, 16S rDNA-based microbiological, non-targeted liver metabolomic, and quantitative real-time polymerase chain reaction analyses to explore the intervening effect and mechanism of VC and VD3 on MAFLD by using a high-fat diet (HFD)-induced obese mouse model.Results: Treatment of mice with VC and VD3 efficiently reversed the characteristics of MAFLD, such as obesity, dyslipidemia, insulin resistance, hepatic steatosis, and inflammation. VC and VD3 showed similar beneficial effects as mentioned above in HFD-induced obese mice. Interestingly, VC and VD3 reshaped the gut microbiota composition; improved gut barrier integrity; ameliorated oxidative stress and inflammation in the gut-liver axis; inhibited bile acid salt reflux-related ASBT; activated bile acid synthesis-related CYP7A1, bile acid receptor FXR, and bile acid transportation-related BSEP in the gut-liver axis; and improved bile secretion, thus decreasing the expression of FAS in the liver and efficiently ameliorating MAFLD in mice.Conclusion: Together, the results indicate that the anti-MAFLD activities of VC and VD3 are linked to improved gut-liver interactions via regulation of the gut microbiota and bile acid metabolism, and they may therefore prove useful in treating MAFLD clinically.
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Affiliation(s)
- Qingling Chen
- Clinical School of the Second People’s Hospital, Tianjin Medical University, Tianjin, China
- Department of Gastroenterology and Hepatology, Tianjin Second People’s Hospital, Tianjin, China
| | - Lili Zhao
- Department of Gastroenterology and Hepatology, Tianjin Second People’s Hospital, Tianjin, China
| | - Ling Mei
- Clinical School of the Second People’s Hospital, Tianjin Medical University, Tianjin, China
- Department of Gastroenterology and Hepatology, Tianjin Second People’s Hospital, Tianjin, China
| | - Xiaotong Zhao
- Department of Clinical Laboratory, Tianjin Second People’s Hospital, Tianjin, China
| | - Ping Han
- Clinical School of the Second People’s Hospital, Tianjin Medical University, Tianjin, China
- Department of Gastroenterology and Hepatology, Tianjin Second People’s Hospital, Tianjin, China
| | - Jie Liu
- Department of Gastroenterology and Hepatology, Tianjin Second People’s Hospital, Tianjin, China
| | - Chao Meng
- Department of Clinical Laboratory, Tianjin Second People’s Hospital, Tianjin, China
| | - Ruifang Li
- School of Medicine, Nankai University, Tianjin, China
| | - Rui Zhong
- Department of Neurology, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Kai Wang
- Key Laboratory of Bioactive Materials for the Ministry of Education, College of Life Sciences, Nankai University, Tianjin, China
- *Correspondence: Kai Wang, ; Jia Li,
| | - Jia Li
- Department of Gastroenterology and Hepatology, Tianjin Second People’s Hospital, Tianjin, China
- *Correspondence: Kai Wang, ; Jia Li,
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16
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1,25-Dihydroxycholecalciferol down-regulates 3-mercaptopyruvate sulfur transferase and caspase-3 in rat model of non-alcoholic fatty liver disease. J Mol Histol 2023; 54:119-134. [PMID: 36930413 DOI: 10.1007/s10735-023-10118-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 02/27/2023] [Indexed: 03/18/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the commonest cause of liver morbidity and mortality and has multiple unclear pathogenic mechanisms. Vitamin D deficiency was associated with increased incidence and severity of NAFLD. Increased hepatic expression of 3-mercaptopyruvate sulfur transferase (MPST) and dysregulated hepatocyte apoptosis were involved in NAFLD pathogenesis. We aimed to explore the protective effect of 1,25-Dihydroxycholecalciferol (1,25-(OH)2 D3) against development of NAFLD and the possible underlying mechanisms, regarding hepatic MPST and caspase-3 expression. 60 male adult rats were divided into 4 and 12 week fed groups; each was subdivided into control, high-fat diet (HFD), and HFD + VD. Serum levels of lipid profile parameters, liver enzymes, insulin, glucose, C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), and hepatic levels of malondialdehyde (MDA), total antioxidant capacity (TAC), and reactive oxygen species (ROS) were measured. BMI and HOMA-IR were calculated, and liver tissues were processed for histopathological and immunohistochemical studies. The present study found that 1,25-(OH)2 D3 significantly decreased BMI, HOMA-IR, serum levels of glucose, insulin, liver enzymes, lipid profile parameters, CRP, TNF-α, hepatic levels of MDA, ROS, hepatic expression of MPST, TNF-α, 8-hydroxy-2'-deoxyguanosine (8-OHdG), and caspase-3; and significantly increased hepatic TAC in both HFD-fed groups. In conclusion: Administration of 1,25-(OH)2 D3 with HFD abolished the NAFLD changes associated with HFD in 4-week group, and markedly attenuated the changes in 12-week group. The anti-apoptotic effect via decrement of caspase-3 and MPST expression are novel mechanisms suggested to be implicated in the protective effect of 1,25-(OH)2 D3.
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17
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Torrado-Salmerón C, Guarnizo-Herrero V, Torrado G, Peña MÁ, Torrado-Santiago S, de la Torre-Iglesias PM. Solid dispersions of atorvastatin with Kolliphor RH40: Enhanced supersaturation and improvement in a hyperlipidemic rat model. Int J Pharm 2023; 631:122520. [PMID: 36581105 DOI: 10.1016/j.ijpharm.2022.122520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 11/25/2022] [Accepted: 12/16/2022] [Indexed: 12/27/2022]
Abstract
Atorvastatin is a potent lipid-lowering drug with poor solubility and high presystemic clearance that limits its therapeutic efficacy. The aim of this study was to develop solid dispersions and micellar systems to obtain fast-dissolving atorvastatin systems that enhances their anti-hyperlipidemic effect. Solubility and wettability studies allow the development of solid dispersions with low proportions of croscarmellose sodium as hydrophilic carrier. Solid state characterization studies indicated that the addition of Kolliphor® RH40 surfactant to solid dispersions increases intermolecular hydrogen bonding between drug and polymer chains. Dissolution studies in biorelevant Fasted State Simulate Intestinal Fluid (FaSSIF pH 6.5) medium showed for atorvastatin solid dispersion a supersaturation peak of atorvastatin followed by an aggregation/precipitation process. Only the presence of a surfactant such as Kolliphor® RH40 in atorvastatin micellar system, promotes the presence of micelles that achieve delayed recrystallization. Efficacy studies were carried out using a hyperlipidemic model of rats fed with a high- fat diet. The atorvastatin micellar system at doses of 10 mg/kg, revealed a significant improvement in serum levels of total cholesterol, low-density lipoproteins, and triglycerides compared to atorvastatin raw material. This micellar system also exhibited more beneficial effects on liver steatosis, inflammation and ballooning injury.
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Affiliation(s)
- Carlos Torrado-Salmerón
- Department of Pharmaceutics and Food Technology, Faculty of Pharmacy, Complutense University of Madrid, Plaza Ramón y Cajal s/n, 28040 Madrid, Spain; Instituto Universitario de Farmacia Industrial (IUFI), Complutense University of Madrid, Plaza Ramón y Cajal s/n, 28040 Madrid, Spain.
| | - Víctor Guarnizo-Herrero
- Department of Pharmaceutics and Food Technology, Faculty of Pharmacy, Complutense University of Madrid, Plaza Ramón y Cajal s/n, 28040 Madrid, Spain.
| | - Guillermo Torrado
- Department of Biomedical Science, Faculty of Pharmacy, University of Alcalá de Henares, Ctra Madrid-Barcelona Km 33,600, 28805 Madrid, Spain.
| | - M Ángeles Peña
- Department of Biomedical Science, Faculty of Pharmacy, University of Alcalá de Henares, Ctra Madrid-Barcelona Km 33,600, 28805 Madrid, Spain.
| | - Santiago Torrado-Santiago
- Department of Pharmaceutics and Food Technology, Faculty of Pharmacy, Complutense University of Madrid, Plaza Ramón y Cajal s/n, 28040 Madrid, Spain; Instituto Universitario de Farmacia Industrial (IUFI), Complutense University of Madrid, Plaza Ramón y Cajal s/n, 28040 Madrid, Spain.
| | - Paloma Marina de la Torre-Iglesias
- Department of Pharmaceutics and Food Technology, Faculty of Pharmacy, Complutense University of Madrid, Plaza Ramón y Cajal s/n, 28040 Madrid, Spain; Instituto Universitario de Farmacia Industrial (IUFI), Complutense University of Madrid, Plaza Ramón y Cajal s/n, 28040 Madrid, Spain.
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18
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Ma X, Yan H, Hong S, Yu S, Gong Y, Wu D, Li Y, Xiao H. Gamma-Aminobutyric Acid Promotes Beige Adipocyte Reconstruction by Modulating the Gut Microbiota in Obese Mice. Nutrients 2023; 15:nu15020456. [PMID: 36678326 PMCID: PMC9864545 DOI: 10.3390/nu15020456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 01/10/2023] [Accepted: 01/13/2023] [Indexed: 01/18/2023] Open
Abstract
Given the increasing prevalence of obesity, the white-to-beige adipocyte conversion has attracted interest as a target for obesity treatment. Gamma-aminobutyric acid (GABA) treatment can reduce obesity, but the underlying mechanism remains unclear. Here, we aimed to investigate the mechanism by which GABA triggers weight loss by improving the beiging of inguinal white adipose tissue (iWAT) and the role of gut microbiota in this process. The results showed that GABA reduced body weight and adipose inflammation and promoted the expression of thermogenic genes in the iWAT. The 16S rRNA sequence analysis of gut microbiota showed that GABA treatment increased the relative abundance of Bacteroidetes, Akkermansia, and Romboutsia and reduced that of Firmicutes and Erysipelatoclostridium in obese mice. Additionally, serum metabolomic analysis revealed that GABA treatment increased 3-hydroxybutyrate and reduced oxidized lipid levels in obese mice. Spearman's correlation analysis showed that Akkermansia and Romboutsia were negatively associated with the levels of oxidized lipids. Fecal microbiota transplantation analysis confirmed that the gut microbiota was involved in the white-to-beige adipocyte reconstruction by GABA. Overall, our findings suggest that GABA treatment may promote iWAT beiging through the gut microbiota in obese mice. GABA may be utilized to protect obese people against metabolic abnormalities brought on by obesity and gut dysbiosis.
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Affiliation(s)
- Xiaoyi Ma
- Department of Endocrinology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China
| | - Huanhuan Yan
- Paul C. Lauterbur Research Center for Biomedical Imaging, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
| | - Shubin Hong
- Department of Endocrinology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China
| | - Shuang Yu
- Department of Endocrinology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China
| | - Yingying Gong
- Department of Geriatrics, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China
| | - Dide Wu
- Department of Endocrinology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China
| | - Yanbing Li
- Department of Endocrinology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China
| | - Haipeng Xiao
- Department of Endocrinology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China
- Correspondence:
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19
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Du T, Xiang L, Zhang J, Yang C, Zhao W, Li J, Zhou Y, Ma L. Vitamin D improves hepatic steatosis in NAFLD via regulation of fatty acid uptake and β-oxidation. Front Endocrinol (Lausanne) 2023; 14:1138078. [PMID: 37033263 PMCID: PMC10074590 DOI: 10.3389/fendo.2023.1138078] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Accepted: 03/02/2023] [Indexed: 04/11/2023] Open
Abstract
INTRODUCTION The study aimed to explore the association of serum 25(OH)D3 and hepatic steatosis in non-alcoholic fatty liver disease (NAFLD) patients and to determine whether the effect of vitamin D (VD) is mediated by activation of the peroxisome proliferator-activated receptor α (PPARα) pathway. METHODS The study contained a case-control study, in vivo and in vitro experiments. A case-control study was conducted to compare serum parameters between NAFLD patients and controls and to evaluate the association of 25(OH)D3 and NAFLD. In vivo study, male Wistar rats were randomly divided into control and model groups, fed a standard chow diet and a high-fat diet (HFD), respectively, for 7 weeks to generate an NAFLD model. Then, the rats were treated with VD and a PPARα antagonist (MK886) for 7 weeks. Tissue and serum were collected and assessed by biochemical assays, morphological analysis, histological analysis, and western blot analysis. In vitro, HepG2 cells were incubated with oleic acid (OA) to induce steatosis, which was evaluated by staining. HepG2 cells were pretreated with MK886 followed by calcitriol treatment, and differences in lipid metabolism-related proteins were detected by western blot. RESULTS NAFLD patients were characterized by impaired liver function, dyslipidemia, and insulin resistance. Serum 25(OH)D3 was negatively associated with alanine aminotransferase (ALT) in NAFLD. VD deficiency was a risk factor for patients with no advanced fibrosis. Adequate VD status (25(OH)D3 >20 ng/mL) had a protective effect in patients after adjustment for confounding variables. NAFLD rats showed hyperlipidemia with severe hepatic steatosis, systematic inflammation, and lower serum 25(OH)D3. VD treatment ameliorated hepatic steatosis both in NAFLD rats and OA-induced HepG2 cells. Further, MK886 inhibited the anti-steatosis effect of VD. CONCLUSION The study revealed that an adequate VD level may act as a protective factor in NAFLD and that VD may alleviate hepatic steatosis via the PPARα signaling pathway.
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Affiliation(s)
- Tingwan Du
- Department of Nutrition and Food Hygiene, School of Public Health, Southwest Medical University, Luzhou, China
| | - Lian Xiang
- Department of Nutrition and Food Hygiene, School of Public Health, Southwest Medical University, Luzhou, China
| | - Jingjing Zhang
- Department of Clinical Nutrition, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Chunmei Yang
- Health Management Center, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Wenxin Zhao
- Department of Nutrition and Food Hygiene, School of Public Health, Southwest Medical University, Luzhou, China
| | - Jialu Li
- Department of Nutrition and Food Hygiene, School of Public Health, Southwest Medical University, Luzhou, China
| | - Yong Zhou
- Department of Medical Cell Biology and Genetics, School of Basic Medical Science, Southwest Medical University, Luzhou, China
- *Correspondence: Yong Zhou, ; Ling Ma,
| | - Ling Ma
- Department of Nutrition and Food Hygiene, School of Public Health, Southwest Medical University, Luzhou, China
- Environmental Health Effects and Risk Assessment Key Laboratory of Luzhou, School of Public Health, Southwest Medical University, Luzhou, China
- *Correspondence: Yong Zhou, ; Ling Ma,
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Kolieb E, Maher SA, Shalaby MN, Alsuhaibani AM, Alharthi A, Hassan WA, El-Sayed K. Vitamin D and Swimming Exercise Prevent Obesity in Rats under a High-Fat Diet via Targeting FATP4 and TLR4 in the Liver and Adipose Tissue. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:13740. [PMID: 36360622 PMCID: PMC9656563 DOI: 10.3390/ijerph192113740] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/10/2022] [Revised: 10/16/2022] [Accepted: 10/18/2022] [Indexed: 11/05/2022]
Abstract
The prevalence of obesity has risen in the last decades, and it has caused massive health burdens on people's health, especially metabolic and cardiovascular issues. The risk of vitamin D insufficiency is increased by obesity, because adipose tissue alters both the requirements for and bioavailability of vitamin D. Exercise training is acknowledged as having a significant and long-term influence on body weight control; the favorable impact of exercise on obesity and obesity-related co-morbidities has been demonstrated via various mechanisms. The current work illustrated the effects of vitamin D supplementation and exercise on obesity induced by a high-fat diet (HFD) and hepatic steatosis in rats and explored how fatty acid transport protein-4 (FATP4) and Toll-like receptor-4 antibodies (TLR4) might be contributing factors to obesity and related hepatic steatosis. Thirty male albino rats were divided into five groups: group 1 was fed a normal-fat diet, group 2 was fed an HFD, group 3 was fed an HFD and given vitamin D supplementation, group 4 was fed an HFD and kept on exercise, and group 5 was fed an HFD, given vitamin D, and kept on exercise. The serum lipid profile adipokines, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) were analyzed, and the pathological changes in adipose and liver tissues were examined. In addition, the messenger-ribonucleic acid (mRNA) expression of FATP4 and immunohistochemical expression of TLR4 in adipose and liver tissues were evaluated. Vitamin D supplementation and exercise improved HFD-induced weight gain and attenuated hepatic steatosis, along with improving the serum lipid profile, degree of inflammation, and serum adipokine levels. The expression of FATP4 and TLR4 in both adipose tissue and the liver was downregulated; it was noteworthy that the group that received vitamin D and was kept on exercise showed also improvement in the histopathological picture of this group. According to the findings of this research, the protective effect of vitamin D and exercise against obesity and HFD-induced hepatic steatosis is associated with the downregulation of FATP4 and TLR4, as well as a reduction in inflammation.
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Affiliation(s)
- Eman Kolieb
- Medical Physiology Department, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt
| | - Shymaa Ahmed Maher
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt
- Center of Excellence in Molecular and Cellular Medicine (CEMCM), Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt
| | - Mohammed Nader Shalaby
- Biological Sciences and Sports Health Department, Faculty of Physical Education, Suez Canal University, Ismailia 41522, Egypt
| | - Amnah Mohammed Alsuhaibani
- Department of Physical Sport Science, College of Education, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia
| | - Afaf Alharthi
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
| | - Wael A. Hassan
- Department of Pathology, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt
- Department of Basic Sciences, College of Medicine, Sulaiman Alrajhi University, Al Bukayriyah 52726, Saudi Arabia
| | - Karima El-Sayed
- Medical Physiology Department, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt
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21
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Effects of Vitamin D Supplementation on Adipose Tissue Inflammation and NF-κB/AMPK Activation in Obese Mice Fed a High-Fat Diet. Int J Mol Sci 2022; 23:ijms231810915. [PMID: 36142842 PMCID: PMC9506068 DOI: 10.3390/ijms231810915] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 09/14/2022] [Accepted: 09/16/2022] [Indexed: 11/20/2022] Open
Abstract
Adipose tissue expansion is strongly associated with increased adipose macrophage infiltration and adipocyte-derived pro-inflammatory cytokines, contributing to obesity-associated low-grade inflammation. Individuals with vitamin D deficiency have an increased prevalence of obesity and increased circulating inflammatory cytokines. However, the effect of vitamin D supplementation on obesity-induced inflammation remains controversial. Male C57BL/6J mice received a low-fat (10% fat) or high-fat (HF, 60% fat diet) containing 1000 IU vitamin D/kg diet, or HF supplemented with 10,000 IU vitamin D/kg diet for 16 weeks (n = 9/group). Vitamin D supplementation did not decrease HF-increased body weight but attenuated obesity-induced adipose hypertrophy and macrophage recruitment as demonstrated by the number of crown-like structures. Vitamin D supplementation significantly reduced the mRNA expression of CD11c, CD68, and iNOS, specific for inflammatory M1-like macrophages, and decreased serum levels of NO. In addition, significant reductions in pro-inflammatory gene expression of IL-6, MCP-1, and TNFα and mRNA levels of ASC-1, CASP1, and IL-1β involved in NLRP3 inflammasome were found in obese mice supplemented with vitamin D. Vitamin D supplementation significantly increased obesity-decreased AMPK activity and suppressed HF-increased NF-κB phosphorylation in adipose tissue from obese mice. These observed beneficial effects of vitamin D supplementation on adipose tissue expansion, macrophage recruitment, and inflammation might be related to AMPK/NF-κB signaling.
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22
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Harahap IA, Landrier JF, Suliburska J. Interrelationship between Vitamin D and Calcium in Obesity and Its Comorbid Conditions. Nutrients 2022; 14:3187. [PMID: 35956362 PMCID: PMC9370653 DOI: 10.3390/nu14153187] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Revised: 07/24/2022] [Accepted: 07/31/2022] [Indexed: 02/01/2023] Open
Abstract
Obesity has been linked to vitamin D (VD) deficiency and low calcium (CAL) status. In the last decade, dietary supplementation of vitamin D and calcium (VD-CAL) have been extensively studied in animal experiments and human studies. However, the physiological mechanisms remain unknown as to whether the VD-CAL axis improves homeostasis and reduces biomarkers in regulating obesity and other metabolic diseases directly or indirectly. This review sought to investigate their connections. This topic was examined in scientific databases such as Web of Science, Scopus, and PubMed from 2011 to 2021, and 87 articles were generated for interpretation. Mechanistically, VD-CAL regulates from the organs to the blood, influencing insulin, lipids, hormone, cell, and inflammatory functions in obesity and its comorbidities, such as non-alcoholic fatty liver disease, cardiovascular disease, and type-2 diabetes mellitus. Nevertheless, previous research has not consistently shown that simultaneous VD-CAL supplementation affects weight loss or reduces fat content. This discrepancy may be influenced by population age and diversity, ethnicity, and geographical location, and also by degree of obesity and applied doses. Therefore, a larger prospective cohort and randomised trials are needed to determine the exact role of VD-CAL and their interrelationship.
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Affiliation(s)
- Iskandar Azmy Harahap
- Department of Human Nutrition and Dietetics, Poznan University of Life Sciences, Wojska Polskiego St. 31, 60-624 Poznan, Poland;
| | | | - Joanna Suliburska
- Department of Human Nutrition and Dietetics, Poznan University of Life Sciences, Wojska Polskiego St. 31, 60-624 Poznan, Poland;
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23
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Bennour I, Haroun N, Sicard F, Mounien L, Landrier JF. Vitamin D and Obesity/Adiposity—A Brief Overview of Recent Studies. Nutrients 2022; 14:nu14102049. [PMID: 35631190 PMCID: PMC9143180 DOI: 10.3390/nu14102049] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 05/10/2022] [Accepted: 05/11/2022] [Indexed: 12/12/2022] Open
Abstract
Observational studies classically find an inverse relationship between human plasma 25-hydroxyvitamin D concentration and obesity. However, interventional and genetic studies have failed to provide clear conclusions on the causal effect of vitamin D on obesity/adiposity. Likewise, vitamin D supplementation in obese rodents has mostly failed to improve obesity parameters, whereas several lines of evidence in rodents and prospective studies in humans point to a preventive effect of vitamin D supplementation on the onset of obesity. Recent studies investigating the impact of maternal vitamin D deficiency in women and in rodent models on adipose tissue biology programming in offspring further support a preventive metabolically driven effect of vitamin D sufficiency. The aim of this review is to summarize the state of the knowledge on the relationship between vitamin D and obesity/adiposity in humans and in rodents and the impact of maternal vitamin D deficiency on the metabolic trajectory of the offspring.
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Affiliation(s)
- Imene Bennour
- Aix-Marseille Université, C2VN, INRAE, INSERM, 13000 Marseille, France; (I.B.); (N.H.); (F.S.); (L.M.)
| | - Nicole Haroun
- Aix-Marseille Université, C2VN, INRAE, INSERM, 13000 Marseille, France; (I.B.); (N.H.); (F.S.); (L.M.)
| | - Flavie Sicard
- Aix-Marseille Université, C2VN, INRAE, INSERM, 13000 Marseille, France; (I.B.); (N.H.); (F.S.); (L.M.)
- PhenoMARS Aix-Marseille Technology Platform, CriBiom, 13000 Marseille, France
| | - Lourdes Mounien
- Aix-Marseille Université, C2VN, INRAE, INSERM, 13000 Marseille, France; (I.B.); (N.H.); (F.S.); (L.M.)
- PhenoMARS Aix-Marseille Technology Platform, CriBiom, 13000 Marseille, France
| | - Jean-François Landrier
- Aix-Marseille Université, C2VN, INRAE, INSERM, 13000 Marseille, France; (I.B.); (N.H.); (F.S.); (L.M.)
- PhenoMARS Aix-Marseille Technology Platform, CriBiom, 13000 Marseille, France
- Correspondence: ; Tel.: +33-4-9129-4275
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24
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Abd El-Haleim EA, Sallam NA. Vitamin D modulates hepatic microRNAs and mitigates tamoxifen-induced steatohepatitis in female rats. Fundam Clin Pharmacol 2021; 36:338-349. [PMID: 34312906 DOI: 10.1111/fcp.12720] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Accepted: 07/23/2021] [Indexed: 12/26/2022]
Abstract
Tamoxifen (TAM) is a life-saving and cost-effective drug widely used in the prevention and treatment of breast cancer. However, the adverse effects of tamoxifen can lead to non-adherence and poor patient outcomes. Therefore, exploring novel strategies to improve TAM safety profile is crucial. Given the key role that vitamin D (VD) plays in modulating lipid metabolism and inflammation, in addition to its benefits in reducing risk and progression of breast cancer, we evaluated the protective potential of VD against TAM-induced hepatotoxicity focusing on lipid metabolism and microRNAs (miRNAs) regulation. Female rats were pretreated with VD as cholecalciferol (500 IU/kg/day, po) for 4 weeks before receiving TAM (40 mg/kg/day, po) concurrently with VD during the fifth and sixth weeks. Liver histology, lipid profile and expression of genes, proteins, and miRNAs involved in lipid metabolism and inflammation were examined. TAM-induced steatohepatitis was evidenced by elevated liver triglycerides and cholesterol contents, increased serum miRNA-122 level, and ALT activity, in parallel with accumulation of lipid droplets, focal necrosis, and inflammatory cells infiltration in hepatocytes. Prophylactic use of VD mitigated TAM-induced steatohepatitis by modulating key transcription factors in the liver: PPAR-α, Srebf1, and NF-κB and their downstream genes/proteins Fas, CPT-1A, and TNF-α resulting in reduced hepatic lipids and suppressed pro-inflammatory signaling. Notably, VD pretreatment mitigated TAM-induced alterations in the expression of serum miRNA-122, hepatic miRNA-21, and miRNA-33. The combination therapy of VD and TAM has complementary benefits in terms of safety and not only efficacy and should be further investigated clinically.
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Affiliation(s)
- Enas A Abd El-Haleim
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Nada A Sallam
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
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25
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Mu Y, Li J, Kang JH, Eto H, Zai K, Kishimura A, Hyodo F, Mori T, Katayama Y. A Lipid-Based Nanocarrier Containing Active Vitamin D 3 Ameliorates NASH in Mice via Direct and Intestine-Mediated Effects on Liver Inflammation. Biol Pharm Bull 2021; 43:1413-1420. [PMID: 32879216 DOI: 10.1248/bpb.b20-00432] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The gut-liver axis may be involved in non-alcoholic steatohepatitis (NASH) progression. Pathogen-associated molecular patterns leak through the intestinal barrier to the liver via the portal vein to contribute to NASH development. Active vitamin D3 (1,25(OH)2D3) is a potential therapeutic agent to enhance the intestinal barrier. Active vitamin D3 also suppresses inflammation and fibrosis in the liver. However, the adverse effects of active vitamin D3 such as hypercalcemia limit its clinical use. We created a nano-structured lipid carrier (NLC) containing active vitamin D3 to deliver active vitamin D3 to the intestine and liver to elicit NASH treatment. We found a suppressive effect of the NLC on the lipopolysaccharide-induced increase in permeability of an epithelial layer in vitro. Using mice in which NASH was induced by a methionine and choline-deficient diet, we discovered that oral application of the NLC ameliorated the permeability increase in the intestinal barrier and attenuated steatosis, inflammation and fibrosis in liver at a safe dose of active vitamin D3 at which the free form of active vitamin D3 did not show a therapeutic effect. These data suggest that the NLC is a novel therapeutic agent for NASH.
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Affiliation(s)
- Yunmei Mu
- Graduate School of Systems Life Sciences, Kyushu University
| | - Jinting Li
- Graduate School of Systems Life Sciences, Kyushu University
| | - Jeong-Hun Kang
- Division of Biopharmaceutics and Pharmacokinetics, National Cerebral and Cardiovascular Center Research Institute
| | - Hinako Eto
- Department of Advanced Medical Initiatives, Faculty of Medical Sciences, Kyushu University
| | - Khadijah Zai
- Department of Pharmaceutical Science and Technology, Universitas Gadjah Mada
| | - Akihiro Kishimura
- Graduate School of Systems Life Sciences, Kyushu University.,Department of Applied Chemistry, Faculty of Engineering, Kyushu University.,Center for Future Chemistry, Kyushu University.,International Research Center for Molecular System, Kyushu University
| | - Fuminori Hyodo
- Department of Radiology, Frontier Science for Imaging, Gifu University School of Medicine
| | - Takeshi Mori
- Graduate School of Systems Life Sciences, Kyushu University.,Department of Applied Chemistry, Faculty of Engineering, Kyushu University.,Center for Future Chemistry, Kyushu University
| | - Yoshiki Katayama
- Graduate School of Systems Life Sciences, Kyushu University.,Department of Applied Chemistry, Faculty of Engineering, Kyushu University.,Center for Future Chemistry, Kyushu University.,International Research Center for Molecular System, Kyushu University
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26
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Xiong P, Zhu YF. Soy diet for nonalcoholic fatty liver disease: A meta-analysis of randomized controlled trials. Medicine (Baltimore) 2021; 100:e25817. [PMID: 34087824 PMCID: PMC8183754 DOI: 10.1097/md.0000000000025817] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Accepted: 04/13/2021] [Indexed: 01/04/2023] Open
Abstract
INTRODUCTION The efficacy of soy diet for nonalcoholic fatty liver disease remains controversial. We conduct a systematic review and meta-analysis to explore the influence of soy diet vs placebo on the treatment of non-alcoholic fatty liver disease. METHODS We search PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases through October 2020 for randomized controlled trials assessing the efficacy of soy diet vs placebo for nonalcoholic fatty liver disease. This meta-analysis is performed using the random-effect model. RESULTS Five randomized controlled trials are included in the meta-analysis. Overall, compared with control group for nonalcoholic fatty liver disease, soy diet is associated with significantly reduced HOMA-IR (standard mean difference [SMD] = -0.42; 95% confidence interval [CI] = -0.76 to -0.08; P = .01), increased insulin (SMD = -0.64; 95% CI = -0.98 to -0.30; P = .0002) and decreased malondialdehyde (SMD = -0.43; 95% CI = -0.74 to -0.13; P = .005), but demonstrated no substantial impact on body mass index (SMD = 0.17; 95% CI = -0.20 to 0.53; P = .37), alanine aminotransferase (SMD = -0.01; 95% CI = -0.61 to 0.60; P = .98), aspartate-aminotransferase (SMD = 0.01; 95% CI = -0.47 to 0.49; P = .97), total cholesterol (SMD = 0.05; 95% CI = -0.25 to 0.35; P = .73) or low density lipoprotein (SMD = 0; 95% CI = -0.30 to 0.30; P = .99). CONCLUSIONS Soy diet may benefit to alleviate insulin resistance for nonalcoholic fatty liver disease.
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Affiliation(s)
- Pian Xiong
- Department of Infectious Disease, The Fourth Affiliated Hospital Zhejiang University, School of Medicine, Yiwu
| | - Yong-Fen Zhu
- Department of Hepatology and infection, Sir Run Run Shaw Hospital, Affiliated with School of Medicine, Zhejiang University, Hangzhou, China
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27
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Cao Y, Shu XB, Yao Z, Ji G, Zhang L. Is vitamin D receptor a druggable target for non-alcoholic steatohepatitis? World J Gastroenterol 2020; 26:5812-5821. [PMID: 33132636 PMCID: PMC7579753 DOI: 10.3748/wjg.v26.i38.5812] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 08/28/2020] [Accepted: 09/08/2020] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic steatohepatitis (NASH) is a progressed stage of non-alcoholic fatty liver disease, and available therapeutic strategies for NASH are limited. Vitamin D receptor (VDR) is proposed as a druggable target for NASH due to the discovery of vitamin D deficiency in NASH patients. To date, vitamin D supplementation has not consistently conferred expected therapeutic benefits, raising the question of whether VDR can serve as a proper drug target for NASH. It is known that VDR can interact with other ligands such as bile acids in addition to vitamin D, and its expression can be induced by fatty acids, and insulin. It has also been shown that while activation of VDR in hepatic macrophages and hepatic stellate cells resulted in attenuation of hepatic inflammation and fibrosis, activation of VDR in hepatocytes could accelerate lipid accumulation. Thus, the multiplicity of VDR ligands, together with the cell type-specificity of VDR activation, must be taken into consideration in assessing the validity of VDR being a potential druggable target for NASH treatment. To this end, we have evaluated the relationship between VDR activation and various contributing factors, such as gut microbiota, bile acid, fatty acids, and insulin, in addition to vitamin D, with an expectation that a potential drug might be identified that can elicit VDR activation in a tissue- and/or cell type-specific manner and therefore achieving therapeutic benefits in NASH.
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Affiliation(s)
- Ying Cao
- Institute of Digestive Diseases, Longhua Hospital, China-Canada Center of Research for Digestive Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Xiang-Bing Shu
- Institute of Digestive Diseases, Longhua Hospital, China-Canada Center of Research for Digestive Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
- Department of Geratology, Baoshan Branch of Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201999, China
| | - Zemin Yao
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa K1H8M5, Ontario, Canada
| | - Guang Ji
- Institute of Digestive Diseases, Longhua Hospital, China-Canada Center of Research for Digestive Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Li Zhang
- Institute of Digestive Diseases, Longhua Hospital, China-Canada Center of Research for Digestive Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
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28
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Chen T, Zuo X, Wang S, Yu P, Yuan J, Wei S, Chen J, Sun Y, Gao Y, Li X. The effect of vitamin D supplementation on the progression of fibrosis in patients with chronic liver disease: A protocol for a systematic review and meta-analysis. Medicine (Baltimore) 2020; 99:e20296. [PMID: 32384521 PMCID: PMC7220037 DOI: 10.1097/md.0000000000020296] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Accepted: 04/16/2020] [Indexed: 01/18/2023] Open
Abstract
BACKGROUND Hepatic fibrosis (HF) is the common pathological basis of chronic liver disease (CLD). Many data indicate that serum vitamin D (VD) levels in patients with liver fibrosis are significantly lower than those without liver fibrosis, and lower level of serum 1,25(OH)2D3 is also an independent risk factor for patients with liver fibrosis combined with other diseases. VD has the functions of anti-fibrosis, regulating cell proliferation and differentiation, anti-inflammatory, and immune regulation, Therefore, serum 1,25(OH)2D3 level may be negatively correlated with the progression of liver fibrosis. But there is absent convincing evidence-based medicine to confirm the efficacy of VD supplementation for CLD. Thus, we aimed to conduct this meta-analysis to summarize the efficacy of VD supplementation on the progression of fibrosis in patients with CLD. METHODS The study only selects clinical randomized controlled trials of VD supplementation for CLD. We will search each database from the built-in until September 2020. The English literature mainly searches Cochrane Library, Pubmed, EMBASE, and Web of Science. While the Chinese literature comes from CNKI, CBM, VIP, and Wangfang database. Meanwhile, we will retrieve clinical trial registries and gray literature. Two researchers worked independently on literature selection, data extraction and quality assessment. The dichotomous data is represented by relative risk (RR), and the continuous is expressed by mean difference (MD) or standard mean difference (SMD), eventually the data is synthesized using a fixed effect model (FEM) or a random effect model (REM) depending on the heterogeneity. The serum VD level, hepatic function and serological indexes of hepatic fibrosis were evaluated as the main outcomes. While several secondary outcomes were also evaluated in this study. The statistical analysis of this Meta-analysis was conducted by RevMan software version 5.3. RESULTS This meta-analysis will further determine the beneficial efficacy of VD supplementation on the progression of fibrosis in patients with CLD. CONCLUSION This study determines the positive efficacy of VD supplementation for CLD. ETHICS AND DISSEMINATION This review is based solely on a secondary study of published literatures and does not require ethics committee approval. Its conclusion will be disseminated in conference papers, magazines or peer-reviewed journals. REGISTRATION NUMBER INPLASY202040054.
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Affiliation(s)
- Tiantian Chen
- Department of Rheumatology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072
| | - Xiaohong Zuo
- School of basic medical sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137
| | - Shengju Wang
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072
| | - Penglong Yu
- Department of Rheumatology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072
| | - Jie Yuan
- School of basic medical sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137
| | - Shujun Wei
- School of basic medical sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137
| | - Jiayi Chen
- Department of Rheumatology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072
| | - Yue Sun
- School of basic medical sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137
| | - Yongxiang Gao
- College of International Education of Chengdu University of Traditional Chinese Medicine, PR China
| | - Xueping Li
- School of basic medical sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137
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29
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Vitamin D Supplementation Improves Adipose Tissue Inflammation and Reduces Hepatic Steatosis in Obese C57BL/6J Mice. Nutrients 2020; 12:nu12020342. [PMID: 32012987 PMCID: PMC7071313 DOI: 10.3390/nu12020342] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Revised: 01/24/2020] [Accepted: 01/27/2020] [Indexed: 02/07/2023] Open
Abstract
The beneficial effect of vitamin D (VD) supplementation on body weight gain limitation and inflammation has been highlighted in primary prevention mice models, but the long-term effect of VD supplementation in tertiary prevention has never been reported in obesity models. The curative effect of VD supplementation on obesity and associated disorders was evaluated in high-fat- and high-sucrose (HFS)-fed mice. Morphological, histological, and molecular phenotype were characterized. The increased body mass and adiposity caused by HFS diet as well as fat cell hypertrophy and glucose homeostasis were not improved by VD supplementation. However, VD supplementation led to a decrease of HFS-induced inflammation in inguinal adipose tissue, characterized by a decreased expression of chemokine mRNA levels. Moreover, a protective effect of VD on HFS-induced hepatic steatosis was highlighted by a decrease of lipid droplets and a reduction of triglyceride accumulation in the liver. This result was associated with a significant decrease of gene expression coding for key enzymes involved in hepatic de novo lipogenesis and fatty acid oxidation. Altogether, our results show that VD supplementation could be of interest to blunt the adipose tissue inflammation and hepatic steatosis and could represent an interesting nutritional strategy to fight obesity-associated comorbidities.
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30
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Multiple genome analyses reveal key genes in Vitamin C and Vitamin D synthesis and transport pathways are shared. Sci Rep 2019; 9:16811. [PMID: 31727908 PMCID: PMC6856197 DOI: 10.1038/s41598-019-53074-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Accepted: 10/24/2019] [Indexed: 02/06/2023] Open
Abstract
Vitamin C (VC) and vitamin D (VD) have been widely used as the dietary supplements and in treatment of diseases both independently and in combination. Whether there is a connection between their pathways is critical for their therapeutic applications. Using whole-genome expression profiles, we performed multiple measures of associations, networks, eQTL mappings and expressions of key genes of interest in VC and VD functions. Several key genes in their pathways were found to be associated. Gc and Rgn play important roles connecting VC and VD pathways in mice. The r values of expression levels between Gc and Rgn in mouse spleen, liver, lung, and kidney are 0.937, 0.558, 0.901, and 0.617, respectively. The expression QTLs of Gc and Rgn are mapped onto the same locations, i.e., 68-76 MB in chromosome 7 and 26-36 MB in chromosome 9. In humans, there are positive correlations between CYP27B1 and SLC23A1 expression levels in kidney (r = 0.733) and spleen (r = 0.424). SLC23A2 and RXRA are minimally associated in both mouse and human. These data indicate that pathways of VC and VD are not independent but affect each other, and this effect is different between mice and humans during VC and VD synthesis and transportation.
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31
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Mousavi S, Lobo de Sá FD, Schulzke JD, Bücker R, Bereswill S, Heimesaat MM. Vitamin D in Acute Campylobacteriosis-Results From an Intervention Study Applying a Clinical Campylobacter jejuni Induced Enterocolitis Model. Front Immunol 2019; 10:2094. [PMID: 31552040 PMCID: PMC6735268 DOI: 10.3389/fimmu.2019.02094] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Accepted: 08/20/2019] [Indexed: 12/11/2022] Open
Abstract
Human Campylobacter infections are progressively rising and of high socioeconomic impact. In the present preclinical intervention study we investigated anti-pathogenic, immuno-modulatory, and intestinal epithelial barrier preserving properties of vitamin D applying an acute campylobacteriosis model. Therefore, secondary abiotic IL-10−/− mice were perorally treated with synthetic 25-OH-cholecalciferol starting 4 days before peroral Campylobacter jejuni infection. Whereas, 25-OH-cholecalciferol application did not affect gastrointestinal pathogen loads, 25-OH-cholecalciferol treated mice suffered less frequently from diarrhea in the midst of infection as compared to placebo control mice. Moreover, 25-OH-cholecalciferol application dampened C. jejuni induced apoptotic cell responses in colonic epithelia and promoted cell-regenerative measures. At day 6 post-infection, 25-OH-cholecalciferol treated mice displayed lower numbers of colonic innate and adaptive immune cell populations as compared to placebo controls that were accompanied by lower intestinal concentrations of pro-inflammatory mediators including IL-6, MCP1, and IFN-γ. Remarkably, as compared to placebo application synthetic 25-OH-cholecalciferol treatment of C. jejuni infected mice resulted in lower cumulative translocation rates of viable pathogens from the inflamed intestines to extra-intestinal including systemic compartments such as the kidneys and spleen, respectively, which was accompanied by less compromised colonic epithelial barrier function in the 25-OH-cholecalciferol as compared to the placebo cohort. In conclusion, our preclinical intervention study provides evidence that peroral synthetic 25-OH-cholecalciferol application exerts inflammation-dampening effects during acute campylobacteriosis.
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Affiliation(s)
- Soraya Mousavi
- Institute of Microbiology, Infectious Diseases and Immunology, Charité - University Medicine Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Fábia Daniela Lobo de Sá
- Institute of Clinical Physiology, Department of Gastroenterology, Infectious Diseases and Rheumatology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Jörg-Dieter Schulzke
- Institute of Clinical Physiology, Department of Gastroenterology, Infectious Diseases and Rheumatology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Roland Bücker
- Institute of Clinical Physiology, Department of Gastroenterology, Infectious Diseases and Rheumatology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Stefan Bereswill
- Institute of Microbiology, Infectious Diseases and Immunology, Charité - University Medicine Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Markus M Heimesaat
- Institute of Microbiology, Infectious Diseases and Immunology, Charité - University Medicine Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
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El-Boshy M, BaSalamah MA, Ahmad J, Idris S, Mahbub A, Abdelghany AH, Almaimani RA, Almasmoum H, Ghaith MM, Elzubier M, Refaat B. Vitamin D protects against oxidative stress, inflammation and hepatorenal damage induced by acute paracetamol toxicity in rat. Free Radic Biol Med 2019; 141:310-321. [PMID: 31255668 DOI: 10.1016/j.freeradbiomed.2019.06.030] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Revised: 06/10/2019] [Accepted: 06/26/2019] [Indexed: 12/21/2022]
Abstract
Acute paracetamol (APAP) toxicity is a leading cause of liver, and less commonly renal, injuries through oxidative stress and inflammation. Albeit vitamin D (VD) is a well-known anti-oxidant and anti-inflammatory hormone, there is no report on its potential protective/therapeutic actions against APAP acute toxicity. This study, therefore, measured the interplay between APAP toxicity and the hepatorenal expressions of the VD-metabolising enzymes (Cyp2R1, Cyp27b1 & cyp24a1), receptor (VDR) and binding protein (VDBP) alongside the effects of VD treatment on APAP-induced hepatorenal injuries. Thirty-two male rats were distributed equally into negative (NC) and positive (PC) controls besides VD prophylactic (P-VD) and therapeutic (T-VD) groups. All groups, except the NC, received a single oral dose of APAP (1200 mg/kg). The P-VD also received by intraperitoneal injection two cycles of VD3 (1000 IU/Kg/day; 5 days/week) prior to, and a third round after, APAP administration. Similarly, the T-VD group received VD3 (3000 IU/Kg/day) for five successive days post-APAP intoxication. Euthanasia was on the sixth day post-APAP toxicity. The PC group had marked alterations in the hepatorenal biochemical parameters, upregulation in cellular cleaved caspase-3 as well as pronounced increase in the numbers of apoptotic/necrotic cells by TUNEL technique. The PC group plasma levels of 25-hydroxyvitamin D (25-OH VD) also declined markedly and coincided with significant inhibitions in the expression of Cyp2R1 and Cyp27b1 enzymes and VDR, whereas the VDBP and Cyp24a1 increased substantially, in the hepatorenal tissues at the gene and protein levels compared with the NC group. Coherently, the lipid peroxidation marker (MDA) and pro-inflammatory cytokines (IL1β, IL6, IL17A, IFN-γ & TNF-α) augmented significantly, while the anti-oxidative markers (GSH, GPx & CAT) and anti-inflammatory cytokines (IL10 & IL22) diminished substantially, in the PC hepatorenal tissues. Both VD regimens alleviated the APAP-induced hepatorenal damages and restored the 25-OH VD levels together with the hepatorenal expression of Cyp2R1, Cyp27b1, Cyp24a1, VDR and VDBP. Additionally, MDA and all the targeted pro-inflammatory cytokines declined, whereas all the anti-oxidative and anti-inflammatory markers increased, in both VD groups hepatorenal tissues and the results were significantly different than the PC group. Although the P-VD anti-inflammatory and anti-oxidative stress actions were more pronounced than the T-VD group, the results remained markedly abnormal than the NC group. In conclusion, this report is the first to reveal that the circulatory VD levels alongside the hepatorenal VD-metabolising enzymes and VDR are pathologically altered following acute APAP toxicity. Moreover, the prophylactic protocol showed better anti-oxidative and anti-inflammatory effects than the therapeutic regimen against APAP-induced hepatorenal injuries.
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Affiliation(s)
- Mohamed El-Boshy
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, PO Box 7607, Makkah, Saudi Arabia; Department of Clinical Pathology, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt
| | - Mohammad A BaSalamah
- Pathology Department, Faculty of Medicine, Umm Al-Qura University, Al Abdeyah, Makkah, Saudi Arabia
| | - Jawwad Ahmad
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, PO Box 7607, Makkah, Saudi Arabia
| | - Shakir Idris
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, PO Box 7607, Makkah, Saudi Arabia
| | - Amani Mahbub
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, PO Box 7607, Makkah, Saudi Arabia
| | - Abdelghany H Abdelghany
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, PO Box 7607, Makkah, Saudi Arabia; Department of Anatomy, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Riyad A Almaimani
- Biochemistry Department, Faculty of Medicine, Umm Al-Qura University, Al Abdeyah, PO Box 7607, Makkah, Saudi Arabia
| | - Hussain Almasmoum
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, PO Box 7607, Makkah, Saudi Arabia
| | - Mazen M Ghaith
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, PO Box 7607, Makkah, Saudi Arabia
| | - Mohamed Elzubier
- Biochemistry Department, Faculty of Medicine, Umm Al-Qura University, Al Abdeyah, PO Box 7607, Makkah, Saudi Arabia
| | - Bassem Refaat
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, PO Box 7607, Makkah, Saudi Arabia.
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Jahn D, Dorbath D, Schilling AK, Gildein L, Meier C, Vuille-Dit-Bille RN, Schmitt J, Kraus D, Fleet JC, Hermanns HM, Geier A. Intestinal vitamin D receptor modulates lipid metabolism, adipose tissue inflammation and liver steatosis in obese mice. Biochim Biophys Acta Mol Basis Dis 2019; 1865:1567-1578. [PMID: 30905785 DOI: 10.1016/j.bbadis.2019.03.007] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Revised: 03/06/2019] [Accepted: 03/19/2019] [Indexed: 01/10/2023]
Abstract
OBJECTIVE Hypovitaminosis D is common in the obese population and patients suffering from obesity-associated disorders such as type 2 diabetes and fatty liver disease, resulting in suggestions for vitamin D supplementation as a potential therapeutic option. However, the pathomechanistic contribution of the vitamin D-vitamin D receptor (VDR) axis to metabolic disorders is largely unknown. METHODS We analyzed the pathophysiological role of global and intestinal VDR signaling in diet-induced obesity (DIO) using global Vdr-/- mice and mice re-expressing an intestine-specific human VDR transgene in the Vdr deficient background (Vdr-/- hTg). RESULTS Vdr-/- mice were protected from DIO, hepatosteatosis and metabolic inflammation in adipose tissue and liver. Furthermore, Vdr-/- mice displayed a decreased adipose tissue lipoprotein lipase (LPL) activity and a reduced capacity to harvest triglycerides from the circulation. Intriguingly, all these phenotypes were partially reversed in Vdr-/- hTg animals. This clearly suggested an intestine-based VDR activity on systemic lipid homeostasis. Scrutinizing this hypothesis, we identified the potent LPL inhibitor angiopoietin-like 4 (Angptl4) as a novel transcriptional target of VDR. CONCLUSION Our study suggests a VDR-mediated metabolic cross-talk between gut and adipose tissue, which significantly contributes to systemic lipid homeostasis. These results have important implications for use of the intestinal VDR as a therapeutic target for obesity and associated disorders.
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Affiliation(s)
- Daniel Jahn
- University Hospital Würzburg, Division of Hepatology, Würzburg, Germany
| | - Donata Dorbath
- University Hospital Würzburg, Division of Hepatology, Würzburg, Germany
| | | | - Lisa Gildein
- University Hospital Würzburg, Division of Hepatology, Würzburg, Germany
| | - Chantal Meier
- University of Zürich, Institute of Physiology, Zürich, Switzerland
| | | | - Johannes Schmitt
- University Hospital Würzburg, Division of Hepatology, Würzburg, Germany
| | - Daniel Kraus
- University Hospital Würzburg, Division of Nephrology, Würzburg, Germany
| | - James C Fleet
- Purdue University, Department of Nutrition Science, West Lafayette, IN, USA
| | - Heike M Hermanns
- University Hospital Würzburg, Division of Hepatology, Würzburg, Germany
| | - Andreas Geier
- University Hospital Würzburg, Division of Hepatology, Würzburg, Germany; University Hospital Zürich, Division of Gastroenterology and Hepatology, Zürich, Switzerland.
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