The metabolic basis of nonalcoholic steatohepatitis

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a major cause of chronic liver disease and is associated with significant morbidity and mortality worldwide, with a high incidence in Western countries and non-Western countries that have adopted a Western diet. NAFLD is commonly associated with components of the metabolic syndrome, type 2 diabetes mellitus and cardiovascular disease, suggesting a common mechanistic basis. An inability to metabolically handle free fatty acid overload-metabolic inflexibility-constitutes a core node for NAFLD pathogenesis, with resulting lipotoxicity, mitochondrial dysfunction and cellular stress leading to inflammation, apoptosis and fibrogenesis. These responses can lead to the histological phenotype of nonalcoholic steatohepatitis (NASH) with varying degrees of fibrosis, which can progress to cirrhosis. This perspective review describes the key cellular and molecular mechanisms of NAFLD and NASH, namely an excessive burden of carbohydrates and fatty acids that contribute to lipotoxicity resulting in hepatocellular injury and fibrogenesis. Understanding the extrahepatic dysmetabolic contributors to NASH is crucial for the development of safe, effective and durable treatment approaches for this increasingly common disease.

Keywords: insulin resistance; lipotoxic stress; metabolic inflexibility; mitochondrial dysfunction.

Figure 1

NAFLD is part of a systemic disease with strong associations with components of the metabolic syndrome. Multifactorial metabolic stress has direct effects on multiple tissues and cell types, which then release cytokines, adipokines, hepatokines and pro‐inflammatory extracellular vesicles. These circulating mediators can amplify or reduce the pathologic changes in various target tissues to create a feed‐forward mechanism of disease progression in the case of amplification. NAFLD, nonalcoholic fatty liver disease

Figure 2

Metabolic flexibility requires the body to have the ability to adequately handle fuels and use appropriate substrates at the appropriate times (A). Inability to maintain homeostatic control to handle fuel needs and appropriately use substrates tips the energy balance scale towards higher intake and storage, ultimately leading to lipotoxic cell stress (B)

Figure 3

Metabolic inflexibility contributes to dysregulated glucose and lipid metabolism in nonalcoholic fatty liver disease. Chronically high sugar and fat intake in the context of obesity and insulin resistance results in a multiorgan dysregulation, resulting in an inability to appropriately dispose of those fuels. Lipolysis is increased in adipose, fat and glucose oxidation is reduced in muscle, and de novo lipogenesis is increased with a concomitant decrease in fat oxidation in the liver. These disruptions ultimately culminate in multiorgan metabolic stress and inflexibility to adapt to a nutrient overload state. Such a state can subsequently impair signalling through canonical fuel‐sensing master regulators such as PPARα and several others. FFA, free fatty acid; PPARα, peroxisome proliferator‐activated receptor α

Figure 4

Insulin resistance and lipotoxicity within the liver are associated with mitochondrial dysfunction, oxidative stress/reactive oxygen species production and ER stress in multiple tissues. These processes contribute to hepatocellular injury, release of inflammatory cytokines, apoptosis and liver fibrogenesis that can progress to cirrhosis. ER, endoplasmic reticulum; FFA, free fatty acid; IL‐1β, interleukin‐1 β; MCP‐1, monocyte chemoattractant protein‐1; TCA, tricarboxylic acid; TNFα, tumour necrosis factor α

Figure 5

Metabolic inflexibility may constitute a core node for NAFLD pathogenesis and its sequelae. Inability to handle fuel substrates results in insulin resistance and an increased flux of FFA and other toxic lipids that lead to lipotoxicity. Consequences of systemic lipotoxicity include dysregulation of fundamental biological pathways including mitochondrial dysfunction, ER stress, inflammation and apoptosis, leading to a cluster of related metabolic diseases. NAFLD has been associated with increased incident T2D by increasing hepatic gluconeogenesis and exacerbating lipid metabolism and release of pro‐inflammatory cytokines with diabetogenic properties. Similarly, T2D may exacerbate progression of NAFLD from NAFL to NASH and cirrhosis. CVD remains the most common cause of death for both NAFLD and T2D. CVD, cardiovascular disease; ER, endoplasmic reticulum; FFA, free fatty acid; NAFL, nonalcoholic fatty liver; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; T2D, type 2 diabetes mellitus