Molecular regulation of lipid metabolism

Consumption of specific dietary fatty acids influences several processes in the body and alters the risk for a number of chronic diseases. In recent years, our understanding of the mechanisms underlying the biological effects of fatty acids has rapidly progressed, thereby providing the foundation for the emerging concept of fatty acid sensing.

Fatty acid sensing can be interpreted as the ability of fatty acids to influence biological processes by serving as signaling molecules. Probably the most widely recognized sensor system for fatty acids is represented by the PPAR (Peroxisome Proliferator Activated Receptor) family. PPARs are transcription factors that are members of the superfamily of nuclear hormone receptors.

Most of our work has concentrated on PPARα and its downstream signaling in liver. Studies on this research theme within the Division of Human Nutrition have shown that PPARα serves as the master regulator of lipid metabolism in liver via regulation of numerous genes. Our work is aimed at trying to further understand the molecular regulation of lipid metabolism in liver and other tissues, partly via elucidating the functional role of PPARα and its targets.

Functional role of PPARα

PPARα serves as the master regulator of hepatic lipid metabolism. Besides mediating the genomic effects of dietary fatty acids, certain chemicals, and hypolipidemic drugs, PPARα also regulates the adaptive response to fasting. Our group has exploited the power of whole genome expression profiling to create a comprehensive map of PPARα-dependent gene regulation in mouse and human liver. These studies have led to the identification of novel targets of PPARα, including G0S2, Vanin-1, and Mannose binding lectin. Current emphasis is on the identification of novel target genes of PPARα.

Angiopoietin-like protein 4 (ANGPTL4)

Circulating triglycerides are cleared by the enzyme lipoprotein lipase (LPL). The activity of LPL is influenced by various physiological stimuli and dictates the rate of fatty acid uptake into tissues. The activity of LPL is carefully controlled by three proteins belonging to the Angiopoietin-like (ANGPTL) family. We have identified ANGPTL4 as the key physiological regulator of LPL in adipose tissue, heart, skeletal muscle and macrophages. Furthermore, we have shown that ANGPTL4 is highly sensitive to regulation by fatty acids via PPARs. Our current research is focused on further characterizing the role of ANGPTL4 in regulation of LPL activity in response to specific stimuli in mice and man. Furthermore, we have a keen interest in understanding the molecular mechanism of LPL inhibition by ANGPTL4.

Hypoxia-induced lipid droplet associated protein (HILPDA)

We identified HILPDA as a novel target of fatty acids and PPARs via two different approaches. First, using expression profiling we found that HILPDA is the most highly induced genes in macrophages incubated with chyle, intralipid and fatty acids. Second, we found that HILPDA is induced by PPARα agonists in liver and by PPARγ agonists in adipocytes. HILPDA encodes a 10 kD protein that has no apparent homology to any other protein. Strikingly, hepatic overexpression of HILPDA in mice led to a 4-fold increase in liver triglyceride storage, concurrent with a significant decrease in hepatic triglyceride secretion. Current studies are directed towards further characterizing the role of HILPDA in lipid metabolism. In particular, we are interested in the interaction of HILPDA with lipid droplets and its potential function as modulator of lipolysis.