FSP27β, a novel fat‐specific protein 27 isoform promoting hepatic steatosis

Potential conflict of interest: Nothing to report. See Article on Page 857 Fat‐specific protein 27 (FSP27), also known as CIDEC in humans, belongs to the cell death‐inducing DNA fragmentation factor like effector (CIDE) family of proteins. Previous studies have shown that FSP27 is a lipid droplet (LD)‐associated protein1 that promotes LD growth3 and triglyceride storage in white adipocytes.1 However, more recent studies have shown that FSP27 is localized not only in LDs but also in other cellular compartments as well.7 Besides adipose tissue it is expressed in muscle and liver.2 FSP27 is transcriptionally regulated by peroxisome proliferator‐activated receptor gamma (PPARγ) during differentiation in adipocytes.1 Yu et al.11 showed that PPARγ overexpression in the liver of PPARγ‐knockout (KO) mice induced FSP27, among other lipogenic genes. Similarly, FSP27 was shown to be highly expressed in animal models of hepatic steatosis.12 Matsusue et al.12 suggested that hepatic steatosis in ob/ob mice is promoted by FSP27, as the knockdown of FSP27 in ob/ob mouse liver ameliorates hepatic steatosis. Furthermore, their liver‐specific ablation of PPARγ markedly suppressed FSP27 expression. Despite these findings, the role of PPARs in hepatic steatosis remains controversial. A study by Vila‐Brau et al.15 found that PPARα, a master regulator of fasting in liver, is not responsible for inducing FSP27 expression. They reported that fasting regulates FSP27 expression in the liver by way of cyclic‐AMP response element binding protein (CREB) to accommodate fatty acid flux in the liver. Another study showed that fasting‐induced hepatic FSP27 expression was suppressed in a mouse deficient in cyclic‐AMP response element binding protein H (CREBH), a liver‐enriched transcription factor that regulates glucose and lipid metabolism. Conversely, FSP27 expression was strongly induced in the liver of liver‐specific transgenic mice overexpressing CREBH, hence suggesting the role of CREBH in regulating FSP27 expression in the liver.16 A new study by Xu et al.17 in this issue of Hepatology shows that CREBH specifically regulates FSP27 expression in the liver. They have shown that FSP27 expression is completely abolished in CREBH‐KO mice, whereas the expression of other CIDE and PAT‐family proteins, Cidea, Cideb, PLIN1, and PLIN2, was unaffected. The authors followed a logical approach to show that the liver expresses FSP27β, an alternative FSP27 isoform. They have demonstrated that the FSP27 gene has an alternative promoter that drives the production of FSP27β and that CREBH directly binds to the CREBH response element in this promoter and activates FSP27β expression. FSP27β differs from the original FSP27 isoform, FSP27α, both in its size and tissue distribution. FSP27β has an additional 10 amino acids at the N‐terminus compared to FSP27α. In addition, FSP27β is the major isoform expressed in the liver and brown adipose tissue, whereas FSP27α is highly expressed in white adipose tissue. Also, PPARγ and CREBH activate FSP27α and FSP27β transcription through distinct promoters in white adipose tissue and liver, respectively. Finally, in contrast to FSP27α, which has a short half life,18 FSP27β is relatively stable, with a prolonged half life. Recent studies have shown that FSP27 (FSP27α) induces triglyceride storage in adipocytes by regulating the catalytic capacity of adipose triglyceride lipase, ATGL, as well as its transcription in adipocytes.8 Xu et al.17 found that FSP27β decreased lipolysis in the liver cells, suggesting that FSP27β caused triglyceride accumulation in hepatocytes by suppressing lipolysis. Similar to FSP27α, FSP27β associates with LDs and stimulates the droplet growth, suggesting redundant functions of the two isoforms. Based on mRNA levels, Xu et al. have proposed that FSP27β is the major isoform in the liver, yet the comparison of protein expression remains to be determined. Liver‐specific ablation of PPARγ in ob/ob mice abolished FSP27 expression and improved hepatic steatosis.12 Whether PPARγ potentiates FSP27β expression by way of CREBH, or PPARγ regulates CREBH expression itself, remains to be determined (Fig. 1). Also, there is still a possibility that FSP27α also plays a role in triglyceride accumulation in the liver to a lesser extent, compared to FSP27β, but by way of an independent mechanism or under different metabolic conditions. The latter possibility is suggested by the fact that the two isoforms have distinct expression in white and brown adipose tissues,17 indicating their differential roles in lipid handling, as white adipose tissue primarily functions in energy storage, whereas brown adipose tissue plays a role in thermogenesis by breaking down fat.Figure 1: CREBH specifically regulates FSP27β expression in the liver to cause hepatic steatosis.17 Also, hepatic steatosis in leptin‐deficient mice is promoted by the PPARγ target gene FSP27.12 Whether and how PPARγ potentiates FSP27β expression by way of CREBH remains to be determined.In addition to demonstrating that activation of CREBH‐FSP27β induced hepatic TG content, the study by Xu et al.17 suggests that loss of CREBH increases TG content in the liver of fasted mice, even though there was decreased FSP27β expression. Kim et al.20 showed that expressing activated CREBH increase hepatic TG levels in obese mice. The latter study also showed that activated CREBH protein interacts with PPARα to form a functional complex upon fasting to induce FGF21, a hepatic metabolic hormone that regulates whole‐body energy homeostasis.20 Infusion of recombinant FGF21 protein reverses steatohepatitis developed in CREBH‐null mice fed an atherogenic high‐fat diet. How CREBH controls hepatic TG homeostasis through diverse mechanisms under different metabolic conditions remains an open question. Author names in bold designate shared co‐first authorship.