Throughout human history, one of the greatest threats to the survival of our ancestors were the long periods with little to no food. As a consequence, starvation has been a key evolutionary pressure shaping human energy metabolism. The intricate architecture of human energy metabolism undoubtedly served our ancestors well, allowing them to survive long periods of starvation. In the modern world of caloric excess, however, the mechanisms that once helped humans to survive starvation now contribute to the unprecedented growth in obesity and related metabolic diseases. Better understanding of the underlying principles and mechanisms driving the adaptive response to fasting will be valuable in the design of new therapeutic strategies for metabolic diseases.
Two organs that play a central role in the metabolic response to fasting are adipose tissue and the liver. The adipose tissue is the body’s energy depot and releases fatty acids to be used as fuel by other tissues. The liver serves as a true metabolic hub during fasting and is the recipient of a major share of the fatty acids released by the adipose tissue.
Overall, our work is concentrated on elucidating the molecular mechanism that underlie the regulation of lipid metabolism in liver and adipose tissue during fasting and feeding. In the past, we demonstrated the importance of the transcription factor PPARα in the metabolic response to fasting in the liver. Using various human liver model systems in combination with transcriptomics, our work also revealed the importance of PPARα in gene regulation and nutrient metabolism in human liver. In addition, my team elucidated the mechanism responsible for the regulation of fat uptake into adipose tissue during fasting. Specifically, we discovered the protein ANGPTL4 and elucidated its role as a crucial regulator of lipid uptake into adipose tissue by interfering with the function of lipoprotein lipase.
Ongoing work in the lab is concentrated on three key pathways.
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 and characterization of novel target genes of PPARα, as well as on the study of the metabolic effects of a group of synthetic PPAR activators, the perfluorinated carboxylic acids.
B. 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.
C. 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. We found that HILPDA promotes lipid storage in cells by inhibiting the enzyme ATGL and activating the enzyme DGAT. Current studies are directed towards further characterizing the role of HILPDA in lipid metabolism in adipocytes, macrophages and liver cells.