Hypoxia and Non-alcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent and represents a growing challenge in terms of prevention and treatment. Despite its high prevalence, only a small minority of affected patients develops inflammation and subsequently fibrosis and chronic liver disease, while most of them only exhibit simple steatosis. In this context, the full understanding of the mechanisms underlying the development of NAFLD and non-alcoholic steatohepatitis (NASH) is of extreme importance; despite advances in this field, knowledge on the pathogenesis of NAFLD is still incomplete. The 'two-hit' hypothesis is now obsolete, as it is inadequate to explain the several molecular and metabolic changes that take place in NAFLD. The "multiple hit" hypothesis considers multiple insults acting together on genetically predisposed subjects to induce NAFLD and provides a more accurate explanation of NAFLD pathogenesis. Such hits include insulin resistance, hormones secreted from the adipose tissue, nutritional factors, gut microbiota and genetic and epigenetic factors. In this article, we review the factors that form this hypothesis.

Hypoxia-inducible factor 1 (HIF-1) activates the transcription of genes that are involved in crucial aspects of cancer biology, including angiogenesis, cell survival, glucose metabolism and invasion. Intratumoral hypoxia and genetic alterations can lead to HIF-1alpha overexpression, which has been associated with increased patient mortality in several cancer types. In preclinical studies, inhibition of HIF-1 activity has marked effects on tumour growth. Efforts are underway to identify inhibitors of HIF-1 and to test their efficacy as anticancer therapeutics.

Oxygen homeostasis represents an organizing principle for understanding metazoan evolution, development, physiology, and pathobiology. The hypoxia-inducible factors (HIFs) are transcriptional activators that function as master regulators of oxygen homeostasis in all metazoan species. Rapid progress is being made in elucidating homeostatic roles of HIFs in many physiological systems, determining pathological consequences of HIF dysregulation in chronic diseases, and investigating potential targeting of HIFs for therapeutic purposes. Copyright © 2012 Elsevier Inc. All rights reserved.