Nutrient-sensing nuclear receptors PPARα and FXR control liver energy balance

Abstract

The nuclear receptors PPARα (encoded by NR1C1) and farnesoid X receptor (FXR, encoded by NR1H4) are activated in the liver in the fasted and fed state, respectively. PPARα activation induces fatty acid oxidation, while FXR controls bile acid homeostasis, but both nuclear receptors also regulate numerous other metabolic pathways relevant to liver energy balance. Here we review evidence that they function coordinately to control key nutrient pathways, including fatty acid oxidation and gluconeogenesis in the fasted state and lipogenesis and glycolysis in the fed state. We have also recently reported that these receptors have mutually antagonistic impacts on autophagy, which is induced by PPARα but suppressed by FXR. Secretion of multiple blood proteins is a major drain on liver energy and nutrient resources, and we present preliminary evidence that the liver secretome may be directly suppressed by PPARα, but induced by FXR. Finally, previous studies demonstrated a striking deficiency in bile acid levels in malnourished mice that is consistent with results in malnourished children. We present evidence that hepatic targets of PPARα and FXR are dysregulated in chronic undernutrition. We conclude that PPARα and FXR function coordinately to integrate liver energy balance.

Zinc reduces hepatic lipid deposition and activates lipophagy via Zn2+/MTF‐1/PPARα and Ca2+/CaMKKβ/AMPK pathways

“…PPARa is a master regulator of the transcriptional control of genes involved in lipid metabolism and autophagy (37). The PPARa-knockout mouse is partially defective in fastinginduced autophagy; however, the PPARa agonist could induce autophagy and also up-regulate the mRNA levels of the most autophagy-related genes (30).…”

Farnesoid X receptor activation induces the degradation of hepatotoxic 1‐deoxysphingolipids in non‐alcoholic fatty liver disease

“…FXR activation induces the expression of genes involved in lipoprotein metabolism/clearance and represses the activity of genes involved in triglyceride synthesis . The main mechanism mediating these effects is inhibition of lipogenesis and induction of beta‐oxidation . However, the regulatory effects of FXR on 1‐deoxysphingolipid metabolism have never been studied.…”

“…8,9 The main mechanism mediating these effects is inhibition of lipogenesis 10,11 and induction of beta-oxidation. 12 However, the regulatory effects of FXR on 1-deoxysphingolipid metabolism have never been studied.…”

Pathophysiological connections between gallstone disease, insulin resistance, and obesity

“…In hepatocytes, BA‐activated FXR directly decreases CYP7A1 levels by activating a transcriptional system that involves small heterodimer partner 1 (SHP‐1), an atypical nuclear receptor family member lacking DNA‐binding domains. SHP‐1 represses CYP7A1 gene expression by directly inhibiting the activity of liver receptor homolog 1 (LRH‐1), a nuclear receptor that positively regulates CYP7A1 gene expression . Interestingly, FXR also decreases the abundance of sterol regulatory element‐binding protein 1 (SREBP1) at the transcriptional level (Figure ) and by this mean is connected to triglyceride metabolism.…”

“…SHP-1 represses CYP7A1 gene expression by directly inhibiting the activity of liver receptor homolog 1 (LRH-1), a nuclear receptor that positively regulates CYP7A1 gene expression. 9,10 Interestingly, FXR also decreases the abundance of sterol regulatory element-binding protein 1 (SREBP1) at the transcriptional level ( Figure 2) and by this mean is connected to triglyceride metabolism. SREBP1 is a transcription factor that FIGURE 1 Pathophysiological relationships between obesity and gallstone disease: the classical and the new proposed model.…”