Association of vitamin D levels and vitamin D-related gene polymorphisms with liver fibrosis in patients with biopsy-proven nonalcoholic fatty liver disease

Arai, Taeang; Atsukawa, Masanori; Tsubota, Akihito; Koeda, Mai; Yoshida, Yūji; Okubo, Tomomi; Nakagawa, Ai; Itokawa, Norio; Kondo, Chisa; Nakatsuka, Katsuhisa; Masu, Takushi; Kato, Kazúo; Shimada, Noritomo; Hatori, Tsutomu; Emoto, Naoya; Kage, Masayoshi; Iwakiri, Katsuhiko

doi:10.1016/j.dld.2018.12.022

Cited by 41 publications

(46 citation statements)

References 52 publications

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“…By the time hepatitis is clinically apparent, correcting local chronic vitamin E deficiency may be too late, with irreversible fibrosis already present. Although there are clues (46), it is unknown whether liver fat affects disposition and metabolism of the 3 other fat-soluble vitamins in humans, and vitamin E experiments here may serve as a paradigm. Rodents have a different lipoprotein profile than humans (47-49), and serial sampling to detect rapid Figure 6.…”

Section: L I N I C a L M E D I C I N Ementioning

confidence: 99%

Vitamin E sequestration by liver fat in humans

et al. 2020

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BACKGROUND. We hypothesized that obesity-associated hepatosteatosis is a pathophysiological chemical depot for fat-soluble vitamins and altered normal physiology. Using α-tocopherol (vitamin E) as a model vitamin, pharmacokinetics and kinetics principles were used to determine whether excess liver fat sequestered α-tocopherol in women with obesity-associated hepatosteatosis versus healthy controls. METHODS. Custom-synthesized deuterated α-tocopherols (d 3-and d 6-α-tocopherols) were administered to hospitalized healthy women and women with hepatosteatosis under investigational new drug guidelines. Fluorescently labeled α-tocopherol was custom-synthesized for cell studies. RESULTS. In healthy subjects, 85% of intravenous d 6-α-tocopherol disappeared from the circulation within 20 minutes but reappeared within minutes and peaked at 3-4 hours; d 3-and d 6-α-tocopherols localized to lipoproteins. Lipoprotein redistribution occurred only in vivo within 1 hour, indicating a key role of the liver in uptake and re-release. Compared with healthy subjects who received 2 mg, subjects with hepatosteatosis had similar d 6-α-tocopherol entry rates into liver but reduced initial release rates (P < 0.001). Similarly, pharmacokinetics parameters were reduced in hepatosteatosis subjects, indicating reduced hepatic d 6-α-tocopherol output. Reductions in kinetics and pharmacokinetics parameters in hepatosteatosis subjects who received 2 mg were echoed by similar reductions in healthy subjects when comparing 5-and 2-mg doses. In vitro, fluorescentlabeled α-tocopherol localized to lipid in fat-loaded hepatocytes, indicating sequestration. CONCLUSIONS. The unique role of the liver in vitamin E physiology is dysregulated by excess liver fat. Obesity-associated hepatosteatosis may produce unrecognized hepatic vitamin E sequestration, which might subsequently drive liver disease. Our findings raise the possibility that hepatosteatosis may similarly alter hepatic physiology of other fat-soluble vitamins. TRIAL REGISTRATION. ClinicalTrials.gov, NCT00862433.

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Section: L I N I C a L M E D I C I N Ementioning

confidence: 99%

Vitamin E sequestration by liver fat in humans

et al. 2020

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“…The relationship between serum 25(OH)D and liver fibrosis is controversial. Some studies demonstrated an inversely correlation between serum 25(OH)D level and the grade of fibrosis [23,24]. However, a meta-analysis involving 974 NAFLD patients showed that serum vitamin D level might be not associated with the histologic severity of NAFLD [25].…”

Section: Discussionmentioning

confidence: 99%

Association between serum 25-hydroxy vitamin D level and metabolic associated fatty liver disease (MAFLD)—a population-based study

et al. 2021

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“…Since that time many studies have shown that in the liver VDR regulates necro-inflammation and fibrosis[47-50]. Moreover, Arai et al[51] recently demonstrated that, in patients with biopsy-proven NAFLD, polymorphisms of the VDR gene are associated with the severity of liver fibrosis.…”

Section: Role Of Vdrmentioning

confidence: 99%

Overview of studies of the vitamin D/vitamin D receptor system in the development of non-alcoholic fatty liver disease

Cimini

Barchetta

Carotti

et al. 2019

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Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world. NAFLD is known to be associated with obesity, type 2 diabetes, metabolic syndrome and increased cardiovascular events: for these reasons, it is becoming a global public health problem and represents an important challenge in terms of prevention and treatment. The mechanisms behind the pathogenesis of NAFLD are multiple and have not yet been completely unraveled; consequently, at moment there are not effective treatments. In the past few years a large body of evidence has been assembled that attributes an important role in hepatic aberrant fat accumulation, inflammation and fibrosis, to the vitamin D/vitamin D receptor (VD/VDR) axis, showing a strong association between hypovitaminosis D and the diagnosis of NAFLD. However, the data currently available, including clinical trials with VD supplementation, still provides a contrasting picture. The purpose of this editorial is to provide an overview of recent advances in the pathogenesis of NAFLD in relation to VD/VDR. Based on recent data from literature, we focused in particular on the hypothesis that VDR itself, independently from its traditional ligand VD, may have a crucial function in promoting hepatic fat accumulation. This might also offer new possibilities for future innovative therapeutic approaches in the management of NAFLD.

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Association of vitamin D levels and vitamin D-related gene polymorphisms with liver fibrosis in patients with biopsy-proven nonalcoholic fatty liver disease

Cited by 41 publications

References 52 publications

Vitamin E sequestration by liver fat in humans

Vitamin E sequestration by liver fat in humans

Association between serum 25-hydroxy vitamin D level and metabolic associated fatty liver disease (MAFLD)—a population-based study

Overview of studies of the vitamin D/vitamin D receptor system in the development of non-alcoholic fatty liver disease

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