Archives

  • 2018-07
  • 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
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • We also showed that steatosis induced an additional

    2022-12-02

    We also showed that steatosis induced an additional increase of ASK1 activation that was associated to the exacerbation of hepatocyte and liver damage and was unrelated to ER stress. Indeed, several settings, also different to ER stress, can induce ASK1 activation and many of them involve oxidative signals [21]. Consistently, we here found that the lipid-induced ASK1 activation depended on the production of oxidant species (OS) by steatotic HP. Previous researches already correlated the increase of intracellular fatty acids and the promotion of oxidative stress as consequence of the increased lipid catabolism through mitochondrial beta-oxidation [22]. This process is instrumental to the removal of fat but also augments the generation of OS by hepatic mitochondria [22]. The upregulation of UCP2, that critically mediates the augmented susceptibility of fatty liver to I/R damage [4], also induces an increase of OS production by liver mitochondria [5]. Additionally, recent evidences indicate a critical role of NADPH Oxidase 2 in producing oxidative species during I/R injury of fatty rat liver [23] The pathophysiology of hepatic I/R generally involves conditions that encompass OS production also in absence of steatosis [24]. The most relevant of them, in term of entity of oxidative stress, is OS production by activated inflammatory cells, but liver (Z)-4-Hydroxytamoxifen too can produce OS by the uncoupled mitochondrial as consequence of oxygen re-admissions [24]. In this regard, we recently observed that only liver sinusoidal cells (LSECs), but not HP, produce OS upon H/R exposure and are sensitive to oxidative stress [15]. These observations, together with the results of the present study, indicate that intracellular production of OS is not relevant for control HP damage induced by H/R but is, instead, responsible of detrimental effects for steatotic HP. The lipid and OS- induced ASK1 activation, in fact, increases HP damage by inducing an augmented JNK stimulation. JNK is an established mediator of tissue and hepatic injury and it has been found involved in both I/R injury [25] and lipotoxicity [9], [10]. Accordingly, we here found that JNK critically mediated the damage of control and steatotic HP since its inhibition significantly reduced H/R damage. In the specific case of KC, we found that PA treatment was directly responsible to induce ER stress also in normoxic conditions and that ER stress induced ASK1 and then p38 MAPK activation. p38MAPK can produce survival responses and can act as molecular mediator of hepatoprotective conditions (Z)-4-Hydroxytamoxifen [18], [19], [26]. Consistently we showed here that both p38 MAPK or ASK1 inhibition increased the damage of steatotic Kupffer cells exposed to H/R. This indicated that, in contrast to what observed for HP, ASK1 activation has a protective role in steatotic KC. In accordance to that, macrophages obtained from ASK1 KO mice resulted unable to activate p38 MAPK but not JNK and this condition made them more sensitive to LPS induced toxicity [27]. Our results also showed the occurrence of an ASK1-independent activation of p38 MAPK in HP and of an ASK1-independent activation JNK in KC with, respectively, protective and toxic outputs. Indeed hypoxia was already found to activate p38 MAPK [18], [26], and hypoxia and/or lipids were described to stimulate JNK [25], [28]. This indicates that p38 MAPK and JNK maintain a protective and toxic role in the development of H/R damage of, respectively, HP and KC, but that ASK1, by further activating JNK in steatotic HP and p38 MAPK in steatotic KC, induces, in the two different populations of liver cells, the prevalence of toxic or protective responses. The observations obtained “in vivo” in mice fed with HF diet and exposed or not to hepatic I/R, mirrored the results obtained in the cellular models. We observed, in fact, an early activation of ASK1 in KC of steatotic liver, and correspondingly an increased stimulation of p38 MAPK in steatotic liver not exposed to I/R. We also observed that the increased susceptibility of fatty liver to I/R injury, as well as, the augmented inflammation were prevented by ASK1 inhibition. This indicated a correlation between the hepato-protective effects of ASK1 inhibition and its capacity to reduce inflammatory reactions. Consistently, early studies from Serafin et al. showed that the capacity of ischemic preconditioning to protect IR injury of fatty liver, was associated to the inhibition of the release of the pro-inflammatory cytokine IL-1 and to the increased production of the potent anti-inflammatory mediator IL-10 [29]. We showed that exposure of fatty liver to IR was associated to an higher activation of ASK1, JNK and p38 MAPK compared with lean liver. These findings are in partial contrast with what reported by Peralta et al. [8], that described a similar or even reduced stimulation of the ER stress mediators in fatty liver exposed to IR compared to lean liver. It is possible, however, that this discrepancy may be due to the homozygous Ob Zucker rat model of liver steatosis employed in the Peralta study. As most of the genetic model of NAFLD, in fact, the ob/ob animal present a significant hepatic lipid accumulation, but reduced markers of inflammation that does not allow steatosis progression to steatohepatitis [11]. This suggests that the prevention of inflammatory reactions typical of this genetic model might hide the effect of lipids on KC, thus reducing the detection of ER stress dependent signals.