bims-mimeim 2021-04-04 papers

Issue of 2021–04–04
three papers selected by
Matthew C. Sinton, University of Glasgow

Cell Mol Gastroenterol Hepatol. 2021 Mar 30. pii: S2352-345X(21)00063-1. [Epub ahead of print]

Hypoxia via ERK signaling inhibits hepatic PPARα to promote fatty liver.

Raja Gopal Reddy Mooli, Jessica Rodriguez, Shogo Takahashi, Sumeet Solanki, Frank J Gonzalez, Sadeesh K Ramakrishnan, Yatrik M Shah.

BACKGROUND & AIMS: Fatty liver or non-alcoholic fatty liver disease (NAFLD) is the most common liver disease associated with co-morbidities such as insulin resistance, cardiovascular and metabolic diseases. Chronic activation of hypoxic signaling; in particular, hypoxia-inducible factor (HIF)2α promotes NAFLD progression by repressing genes involved in fatty acid β-oxidation through unclear mechanisms. Therefore, we assessed the precise mechanism by which HIF2α promote fatty liver and its physiological relevance in metabolic homeostasis.
METHODS: Primary hepatocytes from VHL (VhlΔHep) and PPARα (Ppara-null) knockout mice that were loaded with fatty acids, murine dietary protocols to induce hepatic steatosis, and fasting-refeeding dietary regimen approaches were used to test our hypothesis.
RESULTS: Inhibiting autophagy using chloroquine did not decrease lipid contents in VhlΔHep primary hepatocytes. Inhibition of ERK using MEK inhibitor decreased lipid contents in primary hepatocytes from a genetic model of constitutive HIF activation and primary hepatocytes loaded with free fatty acids. Moreover, MEK-ERK inhibition potentiated ligand-dependent activation of PPARα. We also show that MEK-ERK inhibition improved diet-induced hepatic steatosis, which is associated with the induction of PPARα target genes. During fasting, fatty acid β-oxidation is induced by PPARα, and refeeding inhibits β-oxidation.
CONCLUSIONS: Overall, our results demonstrate that ERK activated by hypoxia signaling plays a crucial role in fatty acid β-oxidation genes by repressing hepatocyte PPARα signaling.

Keywords: ERK; Fatty liver; HIF; Hypoxia; MEK; PPARα; β-oxidation

DOI: https://doi.org/10.1016/j.jcmgh.2021.03.011

Biology (Basel). 2021 Mar 12. pii: 217. [Epub ahead of print]10(3):

Diet-Induced Obesity Promotes the Upregulation of Fas Expression on T-cells.

Tawanda Maurice Nyambuya, Phiwayinkosi Vusi Dludla, Bongani Brian Nkambule.

This study was conducted to assess the expression of Fas (CD95) and programmed cell death-1 (PD-1) on circulating T-cells in obesity using a diet-induced obesity mouse model. Furthermore, we aimed to determine if there are any associations between metabolic disorders and the expression of T-cell regulatory markers. A total of 12 male C57BL/6 mice were randomized into either a high-fat diet (HFD) or low-fat diet (LFD) group for 8 weeks (n = 6/group). Changes in body weights were monitored on a weekly basis. The lipid, glucose, and hematological profiles, as well as Fas and PD1 expression on the T-cell immunophenotype, were measured after 8 weeks of feeding. The HFD-fed group had a higher percentage weight gain (29.17%) in comparison with the LFD-fed group (21.74%) after the 8-week period. In addition, the HFD group had increased fasting glucose and glucose excursion following a 2-h postprandial period. The levels of total cholesterol were elevated in the HFD group when compared with the LFD group (p < 0.05). Notably, the absolute white cell count (p = 0.0096), neutrophil count (p = 0.0022, lymphocytes (p = 0.0155), and monocyte count (p = 0.0015) were elevated in the HFD group when compared with the LFD-fed group. However, the platelets (0.0680), red cell counts (0.3575), and their indices (p > 0.05) were comparable between the two groups. Interestingly, HFD feeding was associated with elevated expression of Fas on T-cells (p < 0.0001), which positively correlated with body weights (r = 0.93, p = 0.0333). No associations were found between Fas expression and dyslipidemia or fasting blood glucose levels (p > 0.05). The multivariant regression analysis showed that the association between the levels of Fas on T-cells and body weights (coefficient: -1.00, t-value: 19.27, p = 0.0330) was independent of fasting blood glucose, total cholesterol, and lymphocyte count. Lastly, the expression of PD-1 on T-cells was comparable between the two diet groups (p = 0.1822). In all, immune activation, dyslipidemia, and poor glucose control in the early stages of obesity may drive the pathogenesis of metabolic T-cell disorders. Importantly, T-cell dysfunction in obesity is partially mediated by an upregulation of Fas which is independent of dyslipidemia and hyperglycemia.

Keywords: Fas; T-cell dysfunction; diet-induced obesity; metabolic disorders; programmed cell death-1

DOI: https://doi.org/10.3390/biology10030217

Cell Metab. 2021 Mar 26. pii: S1550-4131(21)00113-3. [Epub ahead of print]

Serine metabolism antagonizes antiviral innate immunity by preventing ATP6V0d2-mediated YAP lysosomal degradation.

Serine metabolism promotes tumor oncogenesis and regulates immune cell functions, but whether it also contributes to antiviral innate immunity is unknown. Here, we demonstrate that virus-infected macrophages display decreased expression of serine synthesis pathway (SSP) enzymes. Suppressing the SSP key enzyme phosphoglycerate dehydrogenase (PHGDH) by genetic approaches or by treatment with the pharmaceutical inhibitor CBR-5884 and by exogenous serine restriction enhanced IFN-β-mediated antiviral innate immunity in vitro and in vivo. Mechanistic experiments showed that virus infection or serine metabolism deficiency increased the expression of the V-ATPase subunit ATP6V0d2 by inhibiting S-adenosyl methionine-dependent H3K27me3 occupancy at the promoter. ATP6V0d2 promoted YAP lysosomal degradation to relieve YAP-mediated blockade of the TBK1-IRF3 axis and, thus, enhance IFN-β production. These findings implicate critical functions of PHGDH and the key immunometabolite serine in blunting antiviral innate immunity and also suggest manipulation of serine metabolism as a therapeutic strategy against virus infection.

Keywords: ATP6V0d2; H3K27me3; PHGDH; SAM; YAP; antiviral; serine metabolism

DOI: https://doi.org/10.1016/j.cmet.2021.03.006