PGC-1α negatively regulates hepatic FGF21 expression by modulating the heme/Rev-Erbα axis

Abstract

FGF21 is a hormone produced in liver and fat that dramatically improves peripheral insulin sensitivity and lipid metabolism. We show here that obese mice with genetically reduced levels of a key hepatic transcriptional coactivator, PGC-1␣, have improved wholebody insulin sensitivity with increased levels of hepatic and circulating FGF21. Gain-and loss-of-function studies in primary mouse hepatocytes show that hepatic FGF21 levels are regulated by the expression of PGC-1␣. Importantly, PGC-1␣-mediated reduction of FGF21 expression is dependent on Rev-Erb␣ and the expression of ALAS-1. ALAS-1 is a PGC-1␣ target gene and the rate-limiting enzyme in the synthesis of heme, a ligand for Rev-Erb␣. Modulation of intracellular heme levels mimics the effect of PGC-1␣ on FGF21 expression, and inhibition of heme biosynthesis completely abrogates the down-regulation of FGF21 in response to PGC-1␣. Thus, PGC-1␣ can impact hepatic and systemic metabolism by regulating the levels of a nuclear receptor ligand.aintenance of hepatic energy homeostasis is complex and under precise molecular control. Adaptive changes in enzyme expression levels are often controlled at the level of transcription by nuclear hormone receptors and other transcription factors (1). Members of the peroxisome proliferator activated receptor (PPAR)-gamma coactivator-1 (PGC-1s) family play an important role in the tight regulation of enzyme expression within the liver. Fasting induces PGC-1␣ expression, allowing this protein to coactivate several transcription factors including FOXO1, glucocorticoid receptor, nuclear respiratory factor-1 (NRF-1), hepatocyte nuclear factor-4␣, retinoid-related orphan receptors (RORs), and PPAR␣. This leads to increased expression of key enzymes involved in gluconeogenesis, fatty acid oxidation, heme biosynthesis, and the circadian clock (2-4).The importance of the PGC-1 coactivators in the maintenance of liver metabolism is illustrated in several mouse models. Mice with a tissue-specific loss of one allele of hepatic PGC-1␣ expression exhibit fasting-induced steatosis and develop hepatic insulin resistance on a high-fat diet (5). Hepatic PGC-1␣ levels are increased in mouse models of diabetes and obesity (6-9), and are inversely correlated with insulin resistance in humans (10). Although it is clear that the PGC-1s play a key role in regulating the hepatic response to nutritional cues, the molecular pathways are complex.So far, PGC-1s have been shown only to act as potent positive regulators of transcription, because they promote local chromatinremodeling events and formation of the preinitiation complex (11). PGC-1s recruit histone acetyltransferases (HAT)-containing protein complexes (through interactions with CBP/p300), and the TRAP/Mediator complex (by interacting with TRAP220/Med1) (12) in response to hormonal or physiological cues (reviewed in refs. 3 and 13). PGC-1␣ can associate with proteins that negatively affect its coactivator function (e.g., p160/Mib) (14, 15), but there is no evidence that PGC-1s can directly med...

Fibroblast growth factor 21 regulates energy metabolism by activating the AMPK–SIRT1–PGC-1α pathway

“…Chronic reduction of hepatic PGC-1α expression in mice increased FGF21 expression (27). In this scenario, the metabolic status of the animal resembles that of starvation, when PGC-1α levels are low and FGF21 functions to mediate ketogenesis.…”

The Nuclear Receptor Rev-erbα Regulates Adipose Tissue-specific FGF21 Signaling

“…In addition, Rev-erb␣ has been shown to modulate FGF21 expression in liver (62). Given the circadian expression of Rev-erb␣ in WAT, we hypothesized that the repression by Rev-erb␣ would also be rhythmic.…”

Effects of herbage allowance of native grasslands in purebred and crossbred beef cows: metabolic, endocrine and hepatic gene expression profiles through the gestation–lactation cycle

“…It has been reported that FGF21 mRNA expression and circulating concentrations increased only after long-term fasting in mice (>16 h) when it is important for the regulation of adipose tissue catabolism and torpor, a state of decreased activity and metabolism (Estall et al, 2009). Similarly, Kliewer and Mangelsdorf (2010) indicated that FGF21 stimulates gluconeogenesis and ketogenesis in the context of prolonged fasting and starvation (>7 days fasting in humans) but not in the early stages of fasting.…”