Relationship between adipose tissue dysfunction, vitamin D deficiency and the pathogenesis of non-alcoholic fatty liver disease

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. Its pathogenesis is complex and not yet fully understood. Over the years many studies have proposed various pathophysiological hypotheses, among which the currently most widely accepted is the "multiple parallel hits" theory. According to this model, lipid accumulation in the hepatocytes and insulin resistance increase the vulnerability of the liver to many factors that act in a coordinated and cooperative manner to promote hepatic injury, inflammation and fibrosis. Among these factors, adipose tissue dysfunction and subsequent chronic low grade inflammation play a crucial role. Recent studies have shown that vitamin D exerts an immune-regulating action on adipose tissue, and the growing wealth of epidemiological data is demonstrating that hypovitaminosis D is associated with both obesity and NAFLD. Furthermore, given the strong association between these conditions, current findings suggest that vitamin D may be involved in the relationship between adipose tissue dysfunction and NAFLD. The purpose of this review is to provide an overview of recent advances in the pathogenesis of NAFLD in relation to adipose tissue dysfunction, and in the pathophysiology linking vitamin D deficiency with NAFLD and adiposity, together with an overview of the evidence available on the clinical utility of vitamin D supplementation in cases of NAFLD.

Keywords: Adipokines; Adipose tissue dysfunction; Non-alcoholic fatty liver disease; Non-alcoholic steatohepatitis; Obesity; Steatosis; Vitamin D.

Figure 1

Normal visceral adipose tissue consists of a loose connective tissue that is populated with tightly packed adipocytes. In lean individuals VAT homeostasis is maintained by adiponectin released by adipocytes and by M2 macrophages through the secretion of anti-inflammatory cytokines, such as interleukin (IL)-10 and arginase-1. During obesity, dysfunctional visceral adipose tissue (VAT) undergoes excessive fibrosis and accumulation of inflammatory cells. Active macrophages surround dying adipocytes (DA) in typical “crown-like structures”. Pro-M1 polarized macrophages secrete pro-inflammatory cytokines including TNFα, IL-1β and IL-6, which can promote chronic local and systemic inflammation. VAT secretes a large number of adipokines which could play a pivotal role in development of NAFLD. NAFLD: Non-alcoholic fatty liver disease.