Bile acid synthesis not only produces physiological detergents required for intestinal nutrient absorption, but also plays a critical role in regulating hepatic and whole body metabolic homeostasis. We recently reported that over-expression of cholesterol 7α-hydroxylase (CYP7A1) in the liver resulted in improved metabolic homeostasis in Cyp7a1 transgenic (Cyp7a1-tg) mice (Li et al., Hepatology 2010; 52:678-690 & Li et al., Hepatology 2011; 53:996–1006). This study further investigated the molecular links between bile acid metabolism and lipid homeostasis. Microarray gene profiling revealed that CYP7A1 overexpression led to marked activation of the steroid response element binding protein 2 (SREBP2)-regulated cholesterol metabolic network and absence of bile acid repression of lipogenic gene expression in the liver of Cyp7a1-tg mice. Interestingly, Cyp7a1-tg mice showed significantly elevated hepatic cholesterol synthesis rates but reduced hepatic fatty acid synthesis rates, which was accompanied by increased 14C-glucose-derived acetyl-CoA incorporation into sterols for fecal excretion. Induction of SREBP2 also co-induces intronic microRNA-33a (miR-33a) in the SREBP2 gene in Cyp7a1-tg mice. Overexpression of miR-33a in the liver resulted in decreased bile acid pool, increased hepatic cholesterol content and lowered serum cholesterol in mice. This study suggests that a CYP7A1-SREBP2-miR-33a axis plays a critical role in regulation of hepatic cholesterol, bile acid and fatty acid synthesis. Antagonism of miR-33a may be a potential strategy to increase bile acid synthesis to maintain lipid homeostasis and prevent non-alcoholic fatty liver disease (NAFLD), diabetes and obesity.
Background: Bile acid synthesis plays an important role in nutrient absorption and maintaining metabolic homeostasis under normal physiology. Results: Glucose induces cholesterol 7␣-hydroxylase activity and postprandial bile acid synthesis via insulin signaling and epigenetic mechanisms. Conclusion: Glucose and insulin are major postprandial factors that stimulate bile acid synthesis to maintain hepatic metabolic homeostasis. Significance: Nutrient regulation of bile acid synthesis is impaired in diabetes and obesity.
Timing of the mammalian circadian clock of the suprachiasmatic nucleus (SCN) is regulated by photic input from the retina. Retinorecipient units entrain rhythmicity of SCN pacemaker cells in part through their release of vasoactive intestinal polypeptide (VIP). The underlying nature of this process is conjectural however, as in vivo SCN VIP release has never been measured. Here, SCN microdialysis was used to investigate mechanisms regulating VIP. Hamsters under LD 14:10 exhibited a daily peak in synaptic VIP release near midday. Under constant darkness, this output was arrhythmic. Light and the glutamatergic agonist NMDA stimulated VIP release at night, while the 5-HT1A,7 agonist, 8-OH-DPAT, suppressed release at midday. Thus, SCN VIP activity is stimulated by photic input and inhibited by serotonin.
Daily timing of the mammalian circadian clock of the suprachiasmatic nucleus (SCN) is regulated by photic input from the retina via the retinohypothalamic tract. This signaling is mediated by glutamate which activates SCN retinorecipient units communicating to pacemaker cells in part through the release of gastrin-releasing peptide (GRP). Efferent signaling from the SCN involves another SCN-containing peptide, arginine vasopressin (AVP). It is notable that little is known concerning the mechanisms regulating these peptides, as literature on in vivo peptide release in the SCN is sparse. Here, microdialysis-radioimmunoassay procedures were used to characterize mechanisms controlling GRP and AVP release in the hamster SCN. In animals housed under a 14hr:10hr 24hr LD cycle both peptides exhibited daily fluctuations of release, with levels increasing during the morning to peak around midday. Under constant darkness, this pattern persisted for AVP, but rhythmicity was altered for GRP, characterized by a broad plateau throughout the subjective night and early subjective day. Neuronal release of the peptides was confirmed by their suppression with reverse-microdialysis perfusion of calcium blockers and stimulation with depolarizing agents. Reverse-microdialysis perfusion with the 5-HT 1A,7 agonist, 8-OH-DPAT, during the day significantly suppressed GRP but had little effect on AVP. Also, perfusion with the glutamate agonist NMDA, or exposure to light at night, increased GRP but did not affect AVP. These analyses reveal distinct daily rhythms of SCN peptidergic activity, with GRP but not AVP release attenuated by serotonergic activation that inhibits photic phase-resetting, and activated by glutamatergic and photic stimulation that mediate this phase-resetting. Keywordssuprachiasmatic; microdialysis; neuropeptide; serotonin; glutamate; photic The master circadian clock in mammals is located within the suprachiasmatic nucleus (SCN) of the anterior hypothalamus (Klein et al., 1991;Moore, 1983;Rusak and Zucker 1979). Clock timing is synchronized to the 24 hr light-dark cycle directly by photic signaling relayed from the retina to the SCN via the retinohypothalamic tract (RHT; Johnson et al., 1988;Moore and Lenn 1972;Pickard, 1982), and indirectly from the intergeniculate leaflet via the geniculohypothalamic tract (GHT; Card and Moore, 1982;Johnson et al., 1989). The SCN also receives nonphotic entraining input from the GHT and the midbrain raphe nuclei (Albers and Ferris, 1984;Biello et al., 1994;Marchant et al., 1997;Meyer-Bernstein and Morin, 1996). The mechanism by which this diverse input is processed by the SCN to produce a stably entrained rhythm involves interplay among these systems, including three populations of peptidergic neurons indigenous to the SCN. These include cells producing The SCN photic signaling cascade is initiated by glutamate release from RHT terminals located primarily in the ventral SCN core region. This is confirmed by observations that glutamate in the SCN induces time-dependent phase-s...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.