Coupling lipid synthesis inside the liver to power utilization in muscleCoupling lipid synthesis inside the

Coupling lipid synthesis inside the liver to power utilization in muscle
Coupling lipid synthesis inside the liver to power utilization in muscle by coordinating the activity of two closely connected nuclear receptors. These information implicate alterations in diurnal CDK3 medchemexpress hepatic PPAR-PC(18:018:1) COX-1 web signaling in metabolic disorders like obesity. PPAR promotes FA synthesis in the liver9. Surprisingly, hepatic PPAR over-expression (adenoviral-mediated, adPPAR) reduced circulating triglyceride (TG) and totally free fatty acid (FFA) levels (Fig. 1a). FA uptake and -oxidation had been enhanced in isolated soleus muscle, when compared with control mice (adGFP) (Fig. 1b), suggesting a PPAR-dependent signal couples liver lipid metabolism to muscle FA oxidation. To identify candidate molecules, we performed untargeted liquid chromatography-mass spectrometry (LC-MS) based metabolite profiling of hepatic lipids10,11. Metabolite set enrichment analyses ranked acetyl-CoA carboxylase (AcacaAcc1, a price limiting enzyme in de novo lipogenesis) as a prime altered pathway in the adPPARadGFP comparison (Extended Data Fig. 1a and Extended Data Table 1), consistent having a optimistic correlation of ACC1 and PPARD expression in human livers (Extended Data Fig. 1b). Transient liver-specific Acc1 knockdown (LACC1KD) reduced hepatic TG content material and elevated serum TG and FFA levels (Fig. 1c). FA uptake was decreased in isolated soleus muscle from LACC1KD mice (Fig. 1d). In vivo FA uptake assays revealed that muscle FA uptake was decreased in LACC1KD mice inside the dark feeding cycle, when the lipogenic system is active (ZT18 or 12 am. Zeitgeber time ZT0: lights on at 6 am; ZT12: lights off at six pm) (Fig. 1e). This defect was accompanied by slower clearance of circulating 3H-oleic acid (Fig. 1f). These final results demonstrate that hepatic de novo lipogenesis is linked to muscle FA utilization. Ppard expression oscillated diurnally, peaking at evening, coincident with mRNA levels in the molecular clock Bmal1 (Arntl) inside the liver and in dexamethasone-synchronized major hepatocytes (Extended Information Fig. 2a,b). In liver-conditional Ppard knockout (LPPARDKO) mice, induction of hepatic Acc1 through the dark cycle was abolished; diurnal expression of Acc2, fatty acid synthase (Fasn) and stearoyl-CoA desaturase 1 (Scd1) was also altered (Fig. 2a), indicating PPAR regulates rhythmic lipogenic gene expression in the liver. Daytime restricted feeding reversed expression patterns of all important molecular clocks (Extended Data Fig. 2c)12. Peak mRNA levels of Ppard and lipogenic genes also shifted for the light cycle in manage but not LPPARDKO mice (Fig. 2b). The expression of diglycerol acyltransferase (Dgat1, triglyceride synthesis), choline kinase (Chka, phosphocholine synthesis) and core circadian clock genes were unchanged in LPPARDKO mice (Extended Data Fig. 2a,c). Physique weight, feeding activity and insulin sensitivity were similar involving genotypes (Extended Data Fig. 2d,e and Extended Data Table 2). LPPARDKO reduced muscle FA uptake inside the dark cycle in vivo (Fig. 2c), mirroring final results from LACC1KD mice and demonstrating a functional consequence of this hepatic transcriptional circuitry in muscle physiology.Author Manuscript Author Manuscript Author Manuscript Author ManuscriptNature. Author manuscript; available in PMC 2014 August 22.Liu et al.PageProducts of de novo lipogenesis can exert signaling effects, e.g., palmitoleate as a lipokine and 1- palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine as an endogenous ligand in the nuclear receptor PPAR in hepatocytes13,14. In humans and mice,.