Nonalcoholic fatty liver disease

What’s the skinny?

Currently afflicting more than 30 percent of the U.S. population, nonalcoholic fatty liver disease, or NAFLD, rapidly has emerged as a major epidemic. Although the disease is disproportionately prevalent in Hispanic Americans, increasing incidences in India and Brazil highlight its global impact. NAFLD is the most common cause of liver failure and transplantation and the most prevalent liver disorder in industrialized nations, and it is linked to the development of type 2 diabetes, cardiovascular disease, dyslipidemia and metabolic syndrome. Three sessions at the 2016 American Society for Biochemistry and Molecular Biology annual meeting will provide an update on the signaling pathways that contribute to hepatic dysfunction and NAFLD and insight into the genetic determinants that contribute to the etiology of the disease.

Hepatic lipid signaling

The JNK and hedgehog signaling pathways have become pivotal players in the development and progression of NAFLD. Understanding the prominent role that nuclear receptors play in the transcriptional program that underlies varied disease states including NAFLD has led not only to new information about the molecular mechanisms behind hepatic dysfunction but also to considerations for an attractive therapeutic strategy.

Genetic determinants and extrahepatic complications

Population-based studies and exomewide association studies have enabled researchers to uncover genetic variants that confer susceptibility to NAFLD. These studies, coupled with investigation into the role of fetal hepatic inheritance in the development of metabolic diseases in the offspring of obese parents, have increased our understanding of the complex molecular mechanisms that underlie NAFLD. Significantly, NAFLD increases susceptibility to other metabolic disease states, which has spawned the need for a multipronged therapeutic approach including the use of mitochondrial protonophores.

Metabolic insight into the enzymatic players

Multiple hepatic enzymes, including fatty acid elongases and thioesterases, coordinately regulate lipid homeostasis. Consequently, aberrant catalytic activity of these lipid metabolic enzymes has been shown to confer alterations in fatty acid concentrations that are causally linked to NAFLD. Finally, mounting evidence has established a prominent role of branched-chain amino acid metabolism in multiple pathophysiologic states including the hepatic dysfunction that contributes to the etiology of NAFLD.

Organizers

David D. Moore

David D. Moore, Baylor College of Medicine

Marion Sewer

Marion Sewer, University of California, San Diego