All-trans-retinoic acid ameliorates hepatic steatosis in mice by a novel transcriptional cascade

Abstract

Mice deficient small heterodimer partner (SHP) are protected from diet induced hepatic steatosis due to increased fatty acid oxidation and decreased lipogenesis. The decreased lipogenesis appears to be a direct consequence of very low expression of peroxisome proliferator activated receptor gamma 2 (PPARγ2), a potent lipogenic transcription factor, in the SHP−/− liver. The current study focuses on the identification of a SHP dependent regulatory cascade that controls PPARγ2 gene expression, thereby regulating hepatic fat accumulation. Illumina BeadChip array and real-time polymerase chain reaction were used to identify genes responsible for the linkage between SHP and PPARγ2 using hepatic RNAs isolated from SHP−/− and SHP-overexpressing mice. The initial efforts identify that hairy and enhancer of split 6 (Hes6), a novel transcriptional repressor, is an important mediator of the regulation of PPARγ2 transcription by SHP. The Hes6 promoter is specifically activated by the retinoic acid receptor (RAR) in response to its natural agonist ligand all-trans retinoic acid (atRA), and is repressed by SHP. Hes6 subsequently represses hepatocyte nuclear factor 4 alpha (HNF4α) activated-PPARγ2 gene expression via direct inhibition of the HNF4α transcriptional activity. Furthermore, we provide evidences that atRA treatment or adenovirus-mediated RARα overexpression significantly reduced hepatic fat accumulation in obese mouse models as observed in earlier studies and the beneficial effect is achieved via the proposed transcriptional cascade. Conclusions Our study describes a novel transcriptional regulatory cascade controlling hepatic lipid metabolism that identifies retinoic acid signaling as a new therapeutic approach to non-alcoholic fatty liver diseases.

All-Trans-Retinoic Acid Enhances Mitochondrial Function in Models of Human Liver

“…In agreement with a role of atRA in maintaining lipid homeostasis in the liver, decrease of hepatic atRA concentrations via inhibition of atRA synthesis in mice led to microvesicular vacuolation but without a change in liver triglycerides (Paik et al, 2014). However, in diet-induced obese mice atRA treatment decreased hepatic triglyceride content (Berry and Noy, 2009) and hepatic lipid accumulation (Kim et al, 2014). In contrast, in rats vitamin A deficiency led to increased expression of genes involved in fatty acid metabolism in the liver (McClintick et al, 2006) and decreased liver total phospholipid content and phosphatidylcholine synthesis (Oliveros et al, 2007), demonstrating opposite effects to those observed in mice.…”

“…atRA has been shown to suppress PPARg2 expression and decrease hepatic lipid accumulation in diet-induced obese mice by activating RARa (Kim et al, 2014). After adenoviral overexpression of RARb, atRA treatment increased the expression of fatty acid oxidative genes CPT1a and MCAD in mouse liver and in HepG2 cells (Li et al, 2013).…”

“…Altered vitamin A homeostasis is well documented in alcoholic liver disease, but recent reports associate altered vitamin A homeostasis also with NAFLD and steatosis (Ashla et al, 2010;Kim et al, 2014;Liu et al, 2015;Trasino et al, 2015). For example, human liver biopsies of NAFLD and nonalcoholic steatohepatitis patients demonstrated increased expression of the main enzyme metabolizing atRA, CYP26A1, suggesting that atRA is depleted in livers of these patients (Ashla et al, 2010).…”

Vitamin A Deficiency Causes Hyperglycemia and Loss of Pancreatic β-Cell Mass

“…Numerous experimental studies have determined that VA and retinoids possess anti-obesity and anti-lipogenic properties through transcriptional regulation of relevant genes in liver and adipose tissue (45)(46)(47), but it is unclear whether altered VA metabolism is involved in the pathogenesis of T2D. There is a large body of data demonstrating that insulin resistance alters adipose and renal metabolism of RBP4 (retinol binding protein 4), which paradoxically further promotes insulin resistance and the pathogenesis of T2D (48,49).…”

Association of serum retinoic acid with hepatic steatosis and liver injury in nonalcoholic fatty liver disease

“…In addition, in vivo studies revealed that RA effectively reduced adiposity not only in fat but also in liver through increased triglyceride hydrolysis and fat oxidation (11)(12)(13). Recent findings that show a novel transcriptional regulatory cascade controlling hepatic lipid metabolism in the mouse model identified RA signaling as a new therapeutic approach to NAFLD (14).…”