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The peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is a transcriptional coactivator that controls expression of metabolic/energetic genes, programming cellular responses to nutrient and environmental adaptations such as fasting, cold, or exercise. Unlike other coactivators, PGC-1α contains protein domains involved in RNA regulation such as serine/arginine (SR) and RNA recognition motifs (RRMs). However, the RNA targets of PGC-1α and how they pertain to metabolism are unknown. To address this, we performed enhanced ultraviolet (UV) cross-linking and immunoprecipitation followed by sequencing (eCLIP-seq) in primary hepatocytes induced with glucagon. A large fraction of RNAs bound to PGC-1α were intronic sequences of genes involved in transcriptional, signaling, or metabolic function linked to glucagon and fasting responses, but were not the canonical direct transcriptional PGC-1α targets such as OXPHOS or gluconeogenic genes. Among the top-scoring RNA sequences bound to PGC-1α were Foxo1, Camk1δ, Per1, Klf15, Pln4, Cluh, Trpc5, Gfra1, and Slc25a25 PGC-1α depletion decreased a fraction of these glucagon-induced messenger RNA (mRNA) transcript levels. Importantly, knockdown of several of these genes affected glucagon-dependent glucose production, a PGC-1α-regulated metabolic pathway. These studies show that PGC-1α binds to intronic RNA sequences, some of them controlling transcript levels associated with glucagon action.

One drug may suppress the effects of another. Although knowledge of drug suppression is vital to avoid efficacy-reducing drug interactions or discover countermeasures for chemical toxins, drug-drug suppression relationships have not been systematically mapped. Here, we analyze the growth response of Saccharomyces cerevisiae to anti-fungal compound ("drug") pairs. Among 440 ordered drug pairs, we identified 94 suppressive drug interactions. Using only pairs not selected on the basis of their suppression behavior, we provide an estimate of the prevalence of suppressive interactions between anti-fungal compounds as 17%. Analysis of the drug suppression network suggested that Bromopyruvate is a frequently suppressive drug and Staurosporine is a frequently suppressed drug. We investigated potential explanations for suppressive drug interactions, including chemogenomic analysis, coaggregation, and pH effects, allowing us to explain the interaction tendencies of Bromopyruvate.

Cannabinoid receptor 1 (CB-1) antagonists are potential candidates for treating obesity and metabolic complications. Despite clear metabolic benefits, unwanted side effects in the brain pose issues for patients. With the hope of overcoming this obstacle, CB-1 in peripheral tissues has become a potential drug target. Previous studies had suggested that liver CB-1 would be an excellent target to prevent development of nonalcoholic steatohepatitis (NAFLD). However, in this issue of the JCI, Wang et al. showed that CB-1 was barely detectable in the liver and deletion of CB-1 in hepatocytes provided no metabolic benefits against NAFLD. These contradictory results raise substantial concerns about the potential benefits of peripheral CB-1 blockers against NAFLD., Sources of liver fat in metabolic diseases NAFLD is a continuum of liver pathologies, usually seen in overweight or obese people, that can be described in three progressive stages: (a) [...]

Neurocognitive regression can be observed as the main neurological complications after CABG Vitamin D may help prevent neurodegeneration as it plays an important role in the regulation of neurotrophic factors, neurogenesis, In our study we aimed to evaluate whether the preoperative vitamin-D levels of patients who will undergo CABG surgery have an effect on postoperative neurocognitive functions Between May 2021 and November 2022, 100 patients with ASA 1-3 risk score, aged 18-70 who were scheduled for elective CABG surgery were included in the study. All patient were divided into 2 groups. While Vitamin D insufficiency group has 21-29 ng/ml serum 25(OH)D3 level, Vitamin D deficiency group has less than 20 ng/ml serum 25(OH)D3. Demographic characteristics of the patients, age, gender, BMI, educational status, comorbidities and medications, alcohol abuse, ASA classification, preoperative left ventricular ejection fraction value, preoperative 25 OH vitamin D level, NYHA (New York Heart Association Functional Classification) classification, EuroSCORE 2 values were recorded. MOCA cognitive assessment test was applied to the patients 1 day before the operation and 5-7 days after operation. NIRS monitoring was applied to the patients during the surgery. S100B and CXCL10 Ligand were measured preoperatively and at the postoperative 48th hour. The length of stay of the patients in the intensive care unit and hospital, APACHE2 score in the first 24 hours postoperatively and CASUS score for 5 days postoperatively were also calculated and recorded. 27 cases of POCD; Vitamin D deficiency was detected in 6 of them, and vitamin D deficiency was detected in the remaining 21. When the effect of vitamin D levels on the development of POCD was analyzed; POCD developed in 30% of patients with vitamin D deficiency and in 20% of patients with vitamin D insufficiency POCD developed in 30% of patients with vitamin D deficiency and in 20% of patients with vitamin D insufficiency. Although a higher rate of POCD was observed in patients with vitamin D deficiency.In 27 cases with POCD; mean MV adherence time length of stay in the intensive care unit [p=0.015], length of stay in the hospital were found to be significantly longer. No significant difference was found between cerebral desaturation and POCD development in NIRS monitoring. Median preop S100B values of all patients were 34.51 ,postoperative S100B values were 48.37 ,preop CXCL 10 values were 71.32 and postoperative CXCL 10 values were calculated as 89.33. Although both S100B and CXCL 10 values increased in the postoperative period compared to the preoperative period in all patients, no statistically significant increase was observed in those with vitamin D deficiency compared to the insufficiency (p>0.05). According to the analyzes performed, a negative correlation was found between the postoperative CXCL 10 value and the postoperative MOCA score (p<0.04) In patients who underwent isolated CABG surgery with vitamin D deficiency/deficiency; We have seen that POCD risk factors such as advanced age, HT, DM, especially in deficient ones, are compatible with the literature [ABSTRACT FROM AUTHOR]

Mitochondria provide essential metabolites and adenosine triphosphate (ATP) for the regulation of energy homeostasis. For instance, liver mitochondria are a vital source of gluconeogenic precursors under a fasted state. However, the regulatory mechanisms at the level of mitochondrial membrane transport are not fully understood. Here, we report that a liver-specific mitochondrial inner-membrane carrier SLC25A47 is required for hepatic gluconeogenesis and energy homeostasis. Genome-wide association studies found significant associations between SLC25A47 and fasting glucose, HbA1c, and cholesterol levels in humans. In mice, we demonstrated that liver-specific depletion of SLC25A47 impaired hepatic gluconeogenesis selectively from lactate, while significantly enhancing whole-body energy expenditure and the hepatic expression of FGF21. These metabolic changes were not a consequence of general liver dysfunction because acute SLC25A47 depletion in adult mice was sufficient to enhance hepatic FGF21 production, pyruvate tolerance, and insulin tolerance independent of liver damage and mitochondrial dysfunction. Mechanistically, SLC25A47 depletion leads to impaired hepatic pyruvate flux and malate accumulation in the mitochondria, thereby restricting hepatic gluconeogenesis. Together, the present study identified a crucial node in the liver mitochondria that regulates fasting-induced gluconeogenesis and energy homeostasis. [ABSTRACT FROM AUTHOR]

Background & Aims: Expression of P21, encoded by the CDKN1A gene, has been associated with fibrosis progression in steatotic liver disease (SLD); however, the underlying mechanisms remain unknown. In the present study, we investigated the function of CDKN1A in SLD., Methods: CDKN1A expression levels were evaluated in different patient cohorts with SLD, fibrosis, and advanced chronic liver disease (ACLD). Cdkn1a -/- and Cdkn1a +/+ mice were fed with either a Western diet (WD), a Lieber-DeCarli (LdC) diet plus multiple EtOH (ethanol) binges, or a DuAL diet (metabolic dysfunction-associated fatty liver disease and alcohol-related liver). Primary hepatocytes were isolated and functional assays performed., Results: A significant increase in CDKN1A expression was observed in patients with steatohepatitis and fibrosis (with a positive correlation with both NAFLD Activity Score and fibrosis staging scores), cirrhosis and ACLD. Cdkn1a +/+ mice, fed a DuAL diet exhibited liver injury and cell death increased reactive oxygen species (ROS), and markers of senescence (γH2AX, β-GAL, Cdkn1a/p53 ) contributing to steatosis and inflammation. In contrast, Cdkn1a -/- mutant mice showed a significant decrease in senescence-associated markers as well as in markers of liver injury, hepatic steatosis and an increase in fatty acid oxidation and reduction in free fatty acid uptake as well as de novo lipogenesis. Mechanistically, activation of the AMPK-SIRT3 was observed in Cdkn1a -deleted animals., Conclusions: Cdkn1a deletion protected against preclinical SLD by promoting fatty acid oxidation and preventing free fatty acid uptake and de novo lipogenesis via the AMPK-SIRT3 axis. CDKN1A expression was found to be directly correlated with increased severity of NAFLD Activity Score and fibrosis in patients with SLD. CDKN1A could be a potential theragnostic target for the treatment of metabolic dysregulation in patients with SLD, with and without alcohol consumption., Impact and Implications: Expression of p21, encoded by the CDKN1A gene, has been associated with fibrosis progression in steatotic liver disease (SLD), but the molecular mechanisms remain elusive. Interestingly, in this study we found that Cdkn1a deletion protected against preclinical SLD by promoting fatty acid oxidation and preventing free fatty acid uptake and de novo lipogenesis, via the AMPK-SIRT3 axis. Translationally, Cdkn1a expression was found to be directly correlated with increased severity of NAFLD Activity Score (NAS) and fibrosis in SLD patients, and therefore, CDKN1A might be used potential theragnostic target for the treatment of metabolically induced SLD, with and without alcohol consumption., Competing Interests: The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2024 The Author(s).)