Effects of vitamin D on pro-inflammatory cytokines associated with Non-alcoholic fatty liver disease

ABSTRACT|Non- alcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder in the United States, affecting approximately one-third of the population. The prevalence of NAFLD increases to 90% in morbidly obese individuals. Many studies have shown a negative association between NAFLD and vitamin D levels. In fact, low vitamin D levels were correlated to histological severity, necro-inflammation and fibrosis in NAFLD. Vitamin D is recognized for its anti-inflammatory and anti-proliferative properties and mediates these functions through regulating and interrelating with inflammatory cytokines. We hypothesize that vitamin D may regulate gene expression by methods that would resolve ongoing inflammation in NAFLD by reducing the effects of pro-inflammatory cytokines, such as TNF-α, IL-1β, IL-6, IL-8, and up-regulate the effects of anti-inflammatory cytokine such as IL-10, produced in NAFLD and involve in its progression and severity. In our report these cytokines significantly increase mRNA and protein expression of importin-α3 and cyp24A1 and significantly decrease mRNA and protein expression of VDR, IκBα, and cyp27B1 in HepG-2. Treatment of HepG-2s with calcitriol significantly decrease mRNA and protein expression of importin-α3 and attenuate the effects of pro-inflammatory cytokines to induce importin-α3 mRNA and protein expression. IL-10, which is an anti- inflammatory cytokine, significantly reduced mRNA and protein expression of importin-α3 with or without calcitriol. Moreover, calcitriol up-regulates IкBα by increasing its mRNA and protein expression and attenuating the effects of proinflammatory cytokines to reduce mRNA and protein expression of IкBα in HepG-2s. IL-10 significantly increased mRNA and protein expression of IкBα as well as VDR in HepG-2. The effects of IL-10 on importin-α3, VDR and IкBα were further potentiated by calcitriol. Our data suggested that, under inflammatory conditions, calcitriol plays an inhibitory role in the regulation of NF-кB by decreasing the expression of importin α3 and increasing the expression of IкBα and VDR. Thus, calcitriol reduces the translocation of NF-кB and thereby downgrades its activity. Since NF-кB is the main transcription factor which plays a central role in inflammation and synthesis of pro-inflammatory cytokines; down-regulation of its activity offers an effective therapeutic method for alleviating chronic inflammation involved in the development of NAFLD.

Grantor dc:publisher

Creighton University

Year dc:date.issued

2016

Author dc:creator

• Ayouk, Nypiat Martin

Advisor dc:contributor.advisor

• Agrawal, Devendra K.

Statement dc:rights

• Copyright is retained by the Author. A non-exclusive distribution right is granted to Creighton University and to ProQuest following the publishing model selected above.

Language dc:language.iso

en_US

Handle dc:identifier.uri

http://hdl.handle.net/10504/87593

OAI identifier oai:identifier

oai:cdr.creighton.edu:10504/87593