Advances in Unhealthy Nutrition and Circadian Dysregulation in Pathophysiology of NAFLD

Abstract

Unhealthy diets and lifestyle result in various metabolic conditions including metabolic syndrome and non-alcoholic fatty liver disease (NAFLD). Much evidence indicates that disruption of circadian rhythms contributes to the development and progression of excessive hepatic fat deposition and inflammation, as well as liver fibrosis, a key characteristic of non-steatohepatitis (NASH) or the advanced form of NAFLD. In this review, we emphasize the importance of nutrition as a critical factor in the regulation of circadian clock in the liver. We also focus on the roles of the rhythms of nutrient intake and the composition of diets in the regulation of circadian clocks in the context of controlling hepatic glucose and fat metabolism. We then summarize the effects of unhealthy nutrition and circadian dysregulation on the development of hepatic steatosis and inflammation. A better understanding of how the interplay among nutrition, circadian rhythms, and dysregulated metabolism result in hepatic steatosis and inflammation can help develop improved preventive and/or therapeutic strategies for managing NAFLD.

Keywords: NAFLD; circadian; hepatic steatosis; inflammation; metabolic diseases; nutrition.

Figure 1

The effect of circadian dysregulation in macrophage induced by HFD on liver inflammation in NAFLD. Macrophage itself exhibits diurnal oscillations in expression of clock genes. During NAFLD, disruption of diurnal oscillations of clock genes induced by HFD promotes pro-inflammatory response in macrophage. The inflammatory cytokines such as TNFα, IL-1β, and IL-6 released by macrophage enhance inflammatory response and fat deposition in hepatocytes.

Figure 2

HFD induced circadian dysregulation in adipose tissue promotes the development of NAFLD. In adipose tissue, HFD disrupts circadian rhythm and promotes macrophage activation and infiltration, leading to inflammation and insulin resistance in adipocytes and cause adipocyte dysfunction. Lipolysis is enhanced in dysfunctional adipocytes, releasing large amount of FFAs in circulation, which increase fat accumulation in hepatocytes and activate immune cells such as Kupffer cells in liver. Activated immune cells release tons of inflammatory cytokines including TNFα and IL-6 to promote hepatic inflammation and insulin resistance. In addition, recruited immune cells and increased inflammation activate hepatic stellated cells, which cause collagen deposition and fibrosis. HFD also change the secretion of adipokines mediated by circadian clock. Dysfunctional adipocytes release Resistin and RBP-4, increasing steatosis, inflammation and insulin resistance in liver. HFD induces a leptin resistance condition, that leptin promotes inflammation, activates stellated cells and increase fibrosis in liver. Adiponectin, which can decrease hepatic steatosis, inflammation, insulin resistance, and fibrosis, is reduced in dysfunctional adipocytes induced by HFD. TZD such as rosiglitazone and pioglitazone activate PPARγ, restoring adipose tissue circadian rhythm and lowering inflammation and insulin resistance in adipose tissue, and further decreasing FFAs in circulation and the aspects of NAFLD/NASH.