Metabolic homeostasis requires dynamic catabolic and anabolic processes. Autophagy, an intracellular lysosomal degradative pathway, can rewire cellular metabolism linking catabolic to anabolic processes and thus sustain homeostasis. This is especially relevant in the liver, a key metabolic organ that governs body energy metabolism. Autophagy's role in hepatic energy regulation has just begun to emerge and autophagy seems to have a much broader impact than what has been appreciated in the field. Though classically known for selective or bulk degradation of cellular components or energy-dense macromolecules, emerging evidence indicates autophagy selectively regulates various signaling proteins to directly impact the expression levels of metabolic enzymes or their upstream regulators. Hence, we review three specific mechanisms by which autophagy can regulate metabolism: A) nutrient regeneration, B) quality control of organelles, and C) signaling protein regulation. The plasticity of the autophagic function is unraveling a new therapeutic approach. Thus, we will also discuss the potential translation of promising preclinical data on autophagy modulation into therapeutic strategies that can be used in the clinic to treat common metabolic disorders.

Animal models are vital to the study of transfusion and development of new blood products. Post-transfusion recovery of human blood components can be studied in mice, however, there is a need to identify strains that can best tolerate xenogeneic transfusions, as well as to optimize such protocols. Specifically, the importance of using immunodeficient mice, such as NOD.Cg- Prkdc scid Il2rg tm1Wjl /SzJ (NSG) mice, to study human transfusion has been questioned. In this study, strains of wild-type and NSG mice were compared as hosts for human transfusions with outcomes quantified by flow cytometric analyses of CD235a + erythrocytes, CD45 + leukocytes, and CD41 + CD42b + platelets. Complete blood counts were evaluated as well as serum cytokines by multiplexing methods. Circulating human blood cells were maintained better in NSG than in wild-type mice. Lethargy and hemoglobinuria were observed in the first hours in wild-type mice along with increased pro-inflammatory cytokines/chemokines such as monocyte chemoattractant protein-1, tumor necrosis factor α, keratinocyte-derived chemokine (KC or CXCL1), and interleukin-6, whereas NSG mice were less severely affected. Whole blood transfusion resulted in rapid sequestration and then release of human cells back into the circulation within several hours. This rebound effect diminished when only erythrocytes were transfused. Nonetheless, human erythrocytes were found in excess of mouse erythrocytes in the liver and lungs and had a shorter half-life in circulation. Variables affecting the outcomes of transfused erythrocytes were cell dose and mouse weight; recipient sex did not affect outcomes. The sensitivity and utility of this xenogeneic model were shown by measuring the effects of erythrocyte damage due to exposure to the oxidizer diamide on post-transfusion recovery. Overall, immunodeficient mice are superior models for xenotransfusion as they maintain improved post-transfusion recovery with negligible immune-associated side effects.

Introduction Non‐Alcoholic Fatty Liver Disease (NAFLD)is characterized by progressive accumulation of hepatocellular fat possibly associated with impaired hepatic autophagy function. Our preliminary observation showed altered liver zonation in autophagy‐defective conditions. Whether liver zonation is altered in the condition of NAFLD and whether it has any pathological role in disease progression is unknown. In this study, we used a dietary mouse model of NAFL to examine the status of liver zonation and the signaling pathways regulating the hepatic zonation. Methods Wild type mice were fed a High Fat Diet (HFD) for a duration of 24 weeks with liver samples taken at 1 week, 10 weeks, and 24 weeks. Zonal markers were examined at mRNA and protein level by quantitative polymerase chain reaction and Western blotting. Results We identified significant downregulation of various pericentral markers such asCyp2e1, Cyp1a2, Glul, Oat, and Rhbg. Further investigation into the Cytochrome 450 superfamily of monooxygenases, which are pericentral localized proteins, demonstrated marked downregulation of different Cyp450 genes suggesting that xenobiotics handling may be impaired in HFD fed mice. On the other hand, upregulation of periportal markers such as Cdh1, Gls2, Ctnnbip1 were noted in the HFD liver. Kinetics analysis of periportal markers such as E‐cadherin showed elevated expression as early as 1 week of HFD feeding. Examination of Wnt/β‐ catenin signaling pathway, which defines pericentral metabolic zonation, showed no remarkable changes in expression of Wnt/β‐catenin downstream target genes. Contrary to our expectations, expression of HNF4α which is responsible for the regulation of periportal genes expression was remarkably downregulated at both protein and mRNA level despite elevated pericentral zonal genes. Conclusions We demonstrate that HFD altered the expression of selective periportal and pericentral zonal markers suggesting that HFD has an impact on hepatic spatial heterogeneity in a murine model. As such an observed alteration in the zonation of the HFD liver suggests that the metabolic processes which require zonated conditions may also be altered. HFD mediate downregulation of HNF4α may have an important role in the disturbance of hepatic zonation and disease pathogenesis.