Impact of artificial sunlight therapy on the progress of non-alcoholic fatty liver disease in rats

Background & Aims

Non-alcoholic steatohepatitis (NASH) is recognized as the most severe form of non-alcoholic fatty liver disease, with likely progression to liver cirrhosis and hepatocellular carcinoma. However, there is no unified standard for diagnosis and therapeutics. This study aimed to characterize lipid transfer/metabolic proteins as non-invasive diagnostic markers, and to evaluate the therapeutic effects of phototherapy on the progression of NASH in rats.

Methods

Lewis rats given a choline-deficient and iron-supplemented l-amino acid-defined (CDAA) diet and Zucker fa/fa rats were used as a diet-induced and an obesity-related NASH models, respectively, with or without phototherapy.

Results

Serum apolipoprotein E and low molecular weight-adiponectin levels were gradually reduced and reached the lowest level at fatty liver/NASH stage both in CDAA diet-induced NASH model and in genetically obese model. Total-adiponectin levels were dramatically elevated after NASH was established in CDAA diet-induced NASH model. Phototherapy ameliorated hepatocyte apoptosis, inflammation, fibrosis, and insulin/leptin resistance caused by CDAA diet with alteration of the levels of lipid transfer/metabolic proteins and elevation of the circulating active form of vitamin D₃. Vitamin D₃ supplementation ameliorated NASH progression in CDAA diet-induced NASH model. However, phototherapy failed to ameliorate the obesity and steatosis, suggesting that phototherapy may possess anti-inflammatory/fibrotic activity rather than anti-obesity/steatotic activity.

Conclusions

These results suggest that serum lipid transfer/metabolic proteins and vitamin D₃ status may be effective biomarkers for non-invasive diagnosis of NASH progression, and that phototherapy may be a good complementary therapy for NASH because of its regulation of lipid transfer/metabolic proteins and vitamin D₃.

Introduction

Interest in live-donor related liver transplantation has substantially increased in recent years, in part because of the shortage of cadaveric liver donors [1]. Obesity and hepatic steatosis are becoming increasingly common medical problems in the developed world population, and it has been reported that some of potential donor livers present some degree of steatosis [2], [3], [4]. Therefore, preoperative evaluation of hepatic steatosis is critical for donor selection.

Hepatic steatosis includes alcoholic and non-alcoholic fatty liver disease (NAFLD). Additionally, NAFLD includes both simple fatty liver and non-alcoholic steatohepatitis (NASH), defined by the presence of lobular necroinflammatory activity with or without the presence of perisinusoidal fibrosis on liver biopsy [5]. To date, the only reliable method of differentiating simple steatosis from NASH is by liver biopsy, which is costly and carries some risk to patients.

In our present study, we are focusing on levels of lipid transfer/metabolic proteins in the progression of NASH. It has been demonstrated that apolipoprotein E (apo-E) is one of the mediators for cholesterol transportation [6]. Similar to apo-E, adipose tissue-derived adipokine, adiponectin, possesses the fundamental role of glucose regulation and fatty acid catabolism [7]. In addition, apo-AI, a main component of high-density lipoprotein, is proposed to be a serum marker for liver fibrosis in patients with NASH [8]. These findings remind us that lipid transfer/metabolic proteins may be useful biomarkers for non-invasive diagnosis of NAFLD.

Vitamin D is recognized as the “sunshine vitamin.” Most humans depend on sun exposure to satisfy their requirements for vitamin D, but it can be obtained from fortified food, oily fish, and vitamin D supplements [9]. Solar ultraviolet B photons are absorbed by 7-dehydro-cholesterol in the skin, leading to its transformation to pre-vitamin D₃, which is rapidly converted to vitamin D₃. Once formed, vitamin D₃ is metabolized in the liver to 25-hydroxyvitamin D₃ (25(OH)D₃; calcidiol) and then in the kidney to its biologically active form, 1α, 25-dihydroxyvitamin D₃ (1,25(OH)₂D₃; calcitriol) [10]. In addition to its well-known effects on the skeleton, vitamin D deficiency has been recognized to lead to direct adverse effects on other organ systems. Accumulating research suggests that low 25(OH)D₃ concentrations may be related to increased prevalence of various cancers, autoimmune diseases, and cardiovascular events [11]. Moreover, it has been suggested that circulating concentrations of 25(OH)D₃ may be inversely related to the prevalence of type 2 diabetes [12], metabolic syndrome [13], and to insulin resistance [14]. Targher et al. recently reported that NAFLD patients have a marked decrease in serum 25(OH)D₃ concentration, which is closely associated with histopathological features of NAFLD [15]. The non-classical effects of 1,25(OH)₂D₃ create possible therapeutic applications for immune modulation, inhibition of cell proliferation, and induction of cell differentiation [16]. However, much remains to be learned about the effects of phototherapy and vitamin D status on the progress of NAFLD.

In the present study, we first characterize lipid transfer/metabolic proteins as non-invasive diagnostic markers and next evaluate therapeutic effects of phototherapy in a rat NASH model.