Metabolic drivers of non-alcoholic fatty liver disease

Abstract

Background: The incidence of non-alcoholic fatty liver disease (NAFLD) is rapidly increasing worldwide parallel to the global obesity epidemic. NAFLD encompasses a range of liver pathologies and most often originates from metabolically driven accumulation of fat in the liver, or non-alcoholic fatty liver (NAFL). In a subset of NAFL patients, the disease can progress to non-alcoholic steatohepatitis (NASH), which is a more severe form of liver disease characterized by hepatocyte injury, inflammation, and fibrosis. Significant progress has been made over the past decade in our understanding of NASH pathogenesis, but gaps remain in our mechanistic knowledge of the precise metabolic triggers for disease worsening.

Scope of review: The transition from NAFL to NASH likely involves a complex constellation of multiple factors intrinsic and extrinsic to the liver. This review focuses on early metabolic events in the establishment of NAFL and initial stages of NASH. We discuss the association of NAFL with obesity as well as the role of adipose tissue in disease progression and highlight early metabolic drivers implicated in the pathological transition from hepatic fat accumulation to steatohepatitis.

Major conclusions: The close association of NAFL with features of metabolic syndrome highlight plausible mechanistic roles for adipose tissue health and the release of lipotoxic lipids, hepatic de novo lipogenesis (DNL), and disruption of the intestinal barrier in not only the initial establishment of hepatic steatosis, but also in mediating disease progression. Human genetic variants linked to NASH risk to date are heavily biased toward genes involved in the regulation of lipid metabolism, providing compelling support for the hypothesis that NASH is fundamentally a metabolic disease.

Keywords: Adipose tissue; Fructose; Lipotoxicity; NAFLD; NASH; Obesity.

Figure 1

Risk factors associated with progression from fatty liver to NASH. Obesity, insulin resistance, and excess visceral adiposity are associated with the development of NAFL. Hepatic steatosis can be further exacerbated by overnutrition and consumption of dietary sugars and may also be influenced by genetic risk. FFA flux to the liver combined with increased DNL results in substrate overload and an inability of the liver to properly metabolize lipids. Many factors are hypothesized to play a role in the transition to NASH, including a build-up of lipotoxic or oxidized lipids, disrupted intestinal barrier function, increased immune cell activation, secretion of inflammatory cytokines, and elevated hepatic oxidative stress.