- 1Internal Medicine Research Unit, Pfizer Worldwide Research, Development, and Medical, Cambridge, Massachusetts, USA. Electronic address: firstname.lastname@example.org.
- 2Internal Medicine Research Unit, Pfizer Worldwide Research, Development, and Medical, Cambridge, Massachusetts, USA.
Background: The incidence of nonalcoholic fatty liver disease (NAFLD) is increasing rapidly worldwide in 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 nonalcoholic fatty liver (NAFL). In a subset of people with NAFL, the disease can progress to nonalcoholic 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, yet there are still gaps in our mechanistic understanding of the precise metabolic triggers for disease worsening.
Scope of the review: The transition from NAFL to NASH likely involves a complex constellation of multiple factors, both intrinsic and extrinsic to the liver. This review will focus on the early metabolic events in the establishment of NAFL and initial stages of NASH. We will discuss the association of NAFL with obesity as well as the role of adipose tissue in disease progression and will highlight early metabolic drivers implicated in the pathological transition from hepatic fat accumulation to steatohepatitis.
Conclusions: The close association of NAFL with features of the metabolic syndrome highlight plausible mechanistic roles for adipose tissue health and 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 progression of the disease. Human genetic variants linked to NASH risk to date are heavily biased towards genes involved in regulation of lipid metabolism, providing compelling support for the hypothesis that NASH is fundamentally a metabolic disease.