Multiple Parallel Hits Hypothesis in Nonalcoholic Fatty Liver Disease: Revisited After a Decade.

A decade ago, we hypothesised that multiple parallel hits constitute the pathophysiology of non-alcoholic fatty liver disease (NAFLD). We proposed that hepatic lipotoxicity and multiple events beyond the liver, such as adipose tissue inflammation and gastrointestinal hits including dysbiosis, fuel the evolution of NAFLD. Over the last decade, a plethora of studies have evolved this hypothesis into an established concept. First, adipose tissue serves as a cytokine sink in NAFLD which contributes substantially to the systemic inflammatory state in obesity-related disorders. The degree of adipose tissue inflammation directly correlates with the severity of NAFLD and tissue-specific knockout mice established a critical role of adipose tissue inflammation in experimental NAFLD. The most compelling advance in the last decade fostered our understanding of the gut microbiome in NAFLD. Several NAFLD-associated commensals and metabolites have been identified that influence susceptibility to NAFLD. Furthermore, the diet is increasingly emerging as a fuel of metabolic inflammation in obesity-related disorders and NAFLD which is partly mediated by bacterial communites in the gut. Collectively, the multiple parallel hits concept has gained momentum in NAFLD.