|Fig. 1 from the March 2013 commentary by Vishwajeet Puri: during early stages of fasting, FSP27 is upregulated in the liver by CREB to facilitate storage of fatty acids. At later stages of fasting, FAO is increased, which might upregulate SIRT1 activity that would inactivate and downregulate CREB, thus decreasing FSP27 expression and increasing lipolysis to release fatty acids to be fuel for FAO. Click on the image to see a larger version.
In the March issue of the Journal of Lipid Research, two groups independently present research on fat-specific protein 27, or FSP27, which in mice plays a key role in lipid storage and mitochondrial activity in fat cells.
Localized to lipid droplets and highly expressed in adipose tissues, FSP27 is the mouse equivalent to the human cell death-inducing DFFA-like effector c, or CIDEC. Mice that have the gene for this protein knocked out expend energy faster and are resistant to developing both diabetes and obesity, even when fed a high-fat diet. Understanding how this protein’s expression is controlled could lead to breakthroughs in preventing these often-deadly conditions in humans.
For the first JLR paper on this topic, Anna Vilá-Brau and colleagues from the University of Barcelona studied the protein’s activity in the liver and discovered that fasting could regulate the activity of its gene in a time-dependent manner. In the early stages of withholding food from the mice, Fsp27 gene expression increased, but as time went on, the expression decreased. They also showed that downregulation of the fatty-acid oxidation rate regulates Fsp27 expression.
While attempting to determine which transcriptional factor was controlling activation of the Fsp27 gene, they ruled out peroxisome proliferator-activated receptor α’s (PPAR-α) involvement. Instead, they observed that cyclic adenosine monophosphate response element binding protein, also known as CREB, acted as the activator. Decreased Fsp27 expression also was linked to deactylator sirtuin 1, or SIRT1, and the researchers suggest SIRT1 also could mediate the effect of fatty-acid oxidation, which in turn regulates Fsp27 expression.
In an accompanying commentary, Vishwajeet Puri of the Boston University School of Medicine notes that PPAR-α’s noninvolvement was a surprise, given that it is known as a master regulator of fasting in the liver. Puri explains that Vilá Brau et al.’s results support a new model: upregulation of Fsp27 by a CREB-dependent pathway, followed by fatty-acid oxidation increasing SIRT1 activity. When lipids are broken down, fatty-acid oxidation is enhanced; when fatty-acid oxidation is inhibited, FSP27 activity increases. Puri suggests that the next big question is how fatty-acid oxidation induces SIRT1 activity.
In the other paper about FSP27, Masami Ueno and researchers from the Veterans Affairs Palo Alto Health Care System and Stanford University offer their findings on FSP27’s role in lipid-droplet homeostasis. They used a yeast two-hybrid system, positively identifying a direct interaction between FSP27 and the N-terminus region (front end) of nuclear factor of activated T cells 5, or NFAT5, which turns on osmoprotective and inflammatory genes after the nuclear factor is transported to the nucleus. Through indirect immunofluorescence, the researchers showed that FSP27 can inhibit NFAT5’s travel to the nucleus in a hypertonic environment.
Using a reporter-gene construct, they demonstrated that FSP27 negatively affects NFAT5’s transcriptional activity, which is complementary to reverse transcription-polymerase chain reaction, or RT-CR, results showing that Fsp27 overregulation inhibits endogenous chemokines that activate the immune response and tumor-necrosis factor-α. Obesity and type 2 diabetes have been linked to a chronic, low-grade inflammatory process in the body, and an increased amount of chemokines are expressed in adipose tissue of those with these conditions. So FSP27’s activity and any abnormal process causing overexpression of its gene is of paramount importance to understanding what’s happening when these conditions stress the body.
Mary L. Chang (email@example.com) is managing editor of the Journal of Lipid Research and coordinating journal manager of Molecular & Cellular Proteomics.