PHILADELPHIA - It's no secret that a high-fat diet isn't healthy. Now researchers have discovered a molecular clue as to precisely why that is.
Writing in the Journal of Biological Chemistry, Mitchell Lazar, MD, PhD, the Sylvan Eisman Professor of Medicine and director of the Institute for Diabetes, Obesity, and Metabolism at the Perelman School of Medicine at the University of Pennsylvania, and colleagues, describe that mice lacking a gene-expression-controlling enzyme fed a high-fat diet experience rapid thickening of the heart muscle and heart failure. This molecular link between fat intake and an enzyme tasked with regulating gene expression at least in mice has implications for people on so-called Western diets and combating heart disease. Modulating the enzyme's activity could be a new pharmaceutical target.
The team found that the engineered mice without the enzyme HDAC3 tended to underexpress genes important in fat metabolism and energy production. Essentially, when fed a high-fat diet, these animals' hearts cannot generate enough energy and thus cannot pump blood efficiently.
These same mice tolerate a normal diet as well as non-mutant, normal animals. "HDAC3 is an intermediary that normally protects mice from the ravages of a high-fat diet," says Lazar.
HDAC enzymes control gene expression by regulating the accessibility of chromatin - the DNA and protein structure in which genes reside. Within chromatin, DNA is wound around proteins called histones. Genes in tightly wound chromatin areas are generally inaccessible and suppressed, whereas those in loosely packed areas can be activated.
When an animal eats, its metabolism changes, but food doesn't change a cell's genome. Instead, food modulates the "epigenome," molecular markers on the chromatin that influence gene expression by affecting how tightly DNA is wrapped around its protein scaffolding.
Previously, researchers at the University o
|Contact: Karen Kreeger|
University of Pennsylvania School of Medicine