Liver injury triggers adaptive remodeling of the hepatic transcriptome for repair/regeneration. We demonstrate that this involves particularly profound transcriptomic alterations where acute induction of genes involved in handling of endoplasmic reticulum stress (ERS) is accompanied by partial hepatic dedifferentiation. Importantly, widespread hepatic gene downregulation could not simply be ascribed to cofactor squelching secondary to ERS gene induction, but rather involves a combination of active repressive mechanisms. ERS acts through inhibition of the liver-identity (LIVER-ID) transcription factor (TF) network, initiated by rapid LIVER-ID TF protein loss. In addition, induction of the transcriptional repressor NFIL3 further contributes to LIVER-ID gene repression. Alteration to the liver TF repertoire translates into compromised activity of regulatory regions characterized by the densest co-recruitment of LIVER-ID TFs and decommissioning of BRD4 super-enhancers driving hepatic identity. While transient repression of the hepatic molecular identity is an intrinsic part of liver repair, sustained disequilibrium between the ERS and LIVER-ID transcriptional programs is linked to liver dysfunction as shown using mouse models of acute liver injury and livers from deceased human septic patients.

Background & aims: Despite the presumed importance of preventing and treating micronutrient and mineral deficiencies, it is still not clear how to optimize measurement and administration in critically ill patients. In order to design future comparative trials aimed at optimizing micronutrient and mineral management, an important first step is to gain insight in the current practice of micronutrient, phosphate and magnesium monitoring and administration. Methods: Within the metabolism-endocrinology-nutrition (MEN) section of the European Society of Intensive Care Medicine (ESICM), the micronutrient working group designed a survey addressing current practice in parenteral micronutrient and mineral administration and monitoring. Invitations were sent by the ESICM research department to all ESICM members and past members. Results: Three hundred thirty-four respondents completed the survey, predominantly consisting of physicians (321 [96.1%]) and participants working in Europe (262 [78.4%]). Eighty-one (24.3%

Background Muscle weakness is a frequently occurring complication of sepsis, associated with increased morbidity and mortality. Interestingly, obesity attenuates sepsis‐induced muscle wasting and weakness. As the adipokine leptin is strongly elevated in obesity and has been shown to affect muscle homeostasis in non‐septic conditions, we aimed to investigate whether leptin mediates the protective effect of obesity on sepsis‐induced muscle weakness. Methods In a mouse model of sepsis, we investigated the effects of genetic leptin inactivation in obese mice (leptin‐deficient obese mice vs. diet‐induced obese mice) and of leptin supplementation in lean mice (n = 110). We assessed impact on survival, body weight and composition, markers of muscle wasting and weakness, inflammation, and lipid metabolism. In human lean and overweight/obese intensive care unit (ICU) patients, we assessed markers of protein catabolism (n = 1388) and serum leptin (n = 150). Results Sepsis mortality was highest in leptin‐deficient obese mice (53% vs. 23% in diet‐induced obese mice and 37% in lean mice, P = 0.03). Irrespective of leptin, after 5 days of sepsis, lean mice lost double the amount of lean body mass than obese mice (P < 0.0005). Also, irrespective of leptin, obese mice maintained specific muscle force up to healthy levels (P = 0.3) whereas lean mice suffered from reduced specific muscle force (72% of healthy controls, P < 0.0002). As compared with lean septic mice, both obese septic groups had less muscle atrophy, liver amino acid catabolism, and inflammation with a 50% lower plasma TNFα increase (P < 0.005). Conversely, again mainly irrespective of leptin, obese mice lost double amount of fat mass than lean mice after 5 days of sepsis (P < 0.0001), showed signs of increased lipolysis and ketogenesis, and had higher plasma HDL and LDL lipoprotein concentrations (P ≤ 0.01 for all). Muscle fibre type composition was not altered during sepsis, but a higher atrophy sensitivity of type IIb fibres compared with IIa and IIx fibres was observed, independent of obesity or leptin. After 5 days of critical illness, serum leptin was higher (P < 0.0001) and the net waste of nitrogen (P = 0.006) and plasma urea‐to‐creatinine ratio (P < 0.0001) was lower in overweight/obese compared with lean ICU human patients. Conclusions Leptin did not mediate the protective effect of obesity against sepsis‐induced muscle wasting and weakness in mice. Instead, obesity—independent of leptin—attenuated inflammation, protein catabolism, and dyslipidaemia, pathways that may play a role in the observed muscle protection.

Background : Critically ill patients often develop multiple organ failure accompanied by profound metabolic and endocrine alterations. The pathogenesis is incompletely understood, but the development of cellular stress, including endoplasmic reticulum (ER) stress, might play a pivotal role (1). Indeed, markers of ER stress have been observed in critical illness, both in animal models and human patients, correlating with organ dysfunction (1). ER stress normally activates the unfolded protein response (UPR). The UPR follows a distinct temporal pattern, aimed at restoring ER homeostasis in the short term, but inducing apoptosis whenever ER stress becomes too severe or prolonged. During critical illness, the temporal activation pattern in liver has only been partially studied. In addition, the potential implications for liver function and metabolism are currently unknown. Methods : We quantified the hepatic expression of crucial markers of the 3 UPR branches and of key hepatic transcription factors in a clinically relevant fluid-resuscitated mouse model of sepsis. Mice were sacrificed at 10 hrs, 30 hrs or 3 days after cecal ligation and puncture in comparison with healthy pair-fed mice (n=15 per group per time point). We quantified the same markers in postmortem liver biopsies from patients admitted to the intensive care unit with sepsis (n=64), who died after a median ICU stay of 10 days (IQR 6-20 days), in comparison with matched patients undergoing elective restorative rectal surgery (n=18). Results: In septic mice, the UPR showed a distinct temporal pattern. In the acute phase (10-30 hrs), the PERK, IRE1α and ATF6 branches were all activated (p˂0.01). In the prolonged phase (3 days), the PERK and ATF6 branches were attenuated and only the IRE1α branch remained activated (p˂0.0001). The UPR activation in the acute phase coincided with a significant downregulation of key hepatic transcription factors important for normal liver function and metabolism, including Shp, FXR, Lrh1, PXR, Hnf6 and Foxa2 (p˂0.01). Several transcription factors remained significantly downregulated in the prolonged phase. ALT as liver damage marker correlated directly with several UPR markers and inversely with several transcription factors in the acute phase, but not in the prolonged phase. In postmortem liver biopsies of patients with sepsis, we only observed an upregulation of the IRE1α branch of the UPR, consistent with the pattern in prolonged critically ill mice. Also in patients, this coincided with a repression of several key hepatic transcription factors. Conclusion: The present findings suggest that patients admitted to the intensive care unit with sepsis develop a state of chronic ER stress in the liver, which might hamper normal hepatic function at least in part through the downregulation of key transcription factors. References: 1. Thiessen SE et al. BBA-Mol Basis Dis 2017, 1863 ...