Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • br Results br Discussion The present findings outline

    2021-09-16


    Results
    Discussion The present findings outline a novel regulatory mechanism for fasting-induced ketogenesis, which involves histamine release from mast pathways cu into the hepatic portal system, H1 receptor-mediated stimulation of liver OEA biosynthesis, and recruitment of the nuclear receptor PPAR-α by the combined action of OEA and lipolysis-derived FFAs (Figure 7). Three sets of data support this model. First, fasting increases portal histamine levels in wild-type mice, but not in three mutant mouse strains that lack either mast cells or Hdc. Second, fasting is accompanied by a marked enhancement of liver OEA production, a response that is suppressed by mast cell removal, genetic Hdc silencing, or pharmacological H1 receptor blockade. Finally, experimental interventions that disable histamine release and/or liver OEA biosynthesis also attenuate, but do not completely block, fasting-induced PPAR-α activation and ketogenesis. Notably, the same interventions have no effect on the accumulation of lipolysis-derived FFAs. We found that fasting increases histamine levels in portal blood and concomitantly heightens liver OEA production. These responses are suppressed in two mechanistically distinct models of mast cell deficiency: Cpa3 mice, in which mast cells are eliminated by Cre genotoxicity (Feyerabend et al., 2011), and WBB6F1/J-Kit/Kit/J mice, in which mast cell ablation is caused by impaired Kit signaling and is accompanied by various immune and metabolic deficits (Gutierrez et al., 2015, Feyerabend et al., 2016). Collectively, the results support the hypothesis that mast cells are critically implicated in fasting-induced histamine secretion. Of note, portal histamine levels undergo an ≈200% change in the transition from feeding to fasting (Figures 4A and 4G). This increase is comparable in size to those observed in peripheral plasma of asthmatic patients experiencing challenge-induced bronchoconstriction (Bhat et al., 1976, Belcher et al., 1988), an event in which histamine is known to play an important functional role (Kaliner, 1989). The specific mast cell population(s) involved in fasting-induced histamine release remains to be identified, but the available evidence points to three candidate sites: gastrointestinal mucosa, visceral vasculature, and/or portal tracts and sinusoids of the liver (Farrell et al., 1995, Stead et al., 2006). The distinctive population of mast cells that resides in the gut may be well positioned to fill this role. Indeed, mucosal mast cells are found in close proximity of neural fibers (Stead et al., 1987, Stead et al., 1989), including vagal efferents that are activated during a fast (Berthoud and Patterson, 1996, Berthoud, 2008a, Berthoud, 2008b). Moreover, mucosal mast cells respond to vagal stimulation with increased histamine biosynthesis (Stead et al., 2006) and have been implicated in the monitoring and utilization of dietary fat (Ji et al., 2012, Sato et al., 2016). Further investigations are needed to test these possibilities. The stimulus-dependent production of OEA, like that of most lipid-derived mediators, is regulated in a cell- and tissue-selective manner (Piomelli, 2013). Unlike gut mucosa, where OEA is produced using dietary oleic acid as an obligatory precursor (Schwartz et al., 2008), in the liver this process is ostensibly uncoupled from influx of lipolysis-derived FFAs (compare Figures 1A and 1F). It is possible, therefore, though remains to be demonstrated, that liver cells produce OEA through a pathway similar to that used by brain neurons, namely, via mobilization pathways cu of intracellular calcium and subsequent activation of Pla2g4e, a phospholipase/N-acyltransferase responsible for N-oleoyl-PE production (Piomelli, 2013, Ogura et al., 2016). Consistent with this view, previous studies have documented the presence of functionally active H1 receptors linked to calcium signaling in hepatocytes (Garcia-Sainz et al., 1992) and other cellular constituents of the liver (e.g., endothelial cells) (Nakamura and Murata, 2018). The identification of specific cell type(s) involved in histamine-driven OEA formation will allow testing this hypothesis and is an important objective for future studies.