Cover Story Current Issue
The small intestine, as the primary site of nutrient absorption, integrates signals from dietary components and gut microbiota to coordinate systemic energy balance, metabolism, and glucose homeostasis alongside other tissues such as the pancreas, liver, and brain. Nuclear receptors represent one mechanism by which the intestinal epithelium senses and respond to dietary signals via transcriptional regulation of metabolic programs. The Peroxisome Proliferator Activated Receptors (PPARs), including PPARα, PPARδ, and PPARγ, are lipid-responsive nuclear hormone receptors. PPAR transcriptional activity is highly context-dependent, shaped by the availability and affinity of their lipid ligands and co-regulators as well as by cell and tissue types. Whereas PPARγ and PPARδ are established regulators of glucose homeostasis, acting in white adipose tissue, skeletal muscle, and liver to improve insulin sensitivity, PPARα has been primarily associated with hepatic lipid metabolism, where it promotes fatty acid transport, β-oxidation, and ketogenesis. Due to their roles in lipid metabolism and anti-inflammatory processes, selective PPAR agonists are being actively pursued as therapies in clinical and pre-clinical studies for metabolic diseases. Thus, it is critical to improve our understanding of the context-specific and tissue-specific effects of PPAR signaling.
Current Issue
Loss of energy homeostasis contributes to hepatic damage development in sickle cell disease
Loss of energy homeostasis contributes to hepatic damage development in sickle cell disease
Sickle cell disease (SCD) is characterized by the expression of an abnormal hemoglobin variant (HbS) that promotes distortion and early destruction of red blood cells, resulting in hemolytic anemia, vaso-occlusive crisis, ischemia and, ultimately, tissue damage. Hepatic function is specially compromised in SCD patients; however, the underlying pathological mechanisms remain largely unknown. In the current study, we confirmed the presence of hepatic damage in a murine model of SCD and, through a label free quantitative proteomic approach, we identified significant alterations in protein expression compared to healthy controls. These changes unveiled distinct proteome expression profiles between groups, with molecular alterations linked to impaired hepatic function, anemia, mitochondrial dysfunction, and alteration in lipid metabolism. We also confirmed these novel alterations through molecular and functional analyses, revealing a previously undescribed liver energy homeostasis imbalance, accompanied by accumulation of foam cells. Our findings provide new insights into the complex mechanisms underlying liver disease and potential therapeutic targets in SCD.
Articles in Press
Loss of energy homeostasis contributes to hepatic damage development in sickle cell disease
Loss of energy homeostasis contributes to hepatic damage development in sickle cell disease
Sickle cell disease (SCD) is characterized by the expression of an abnormal hemoglobin variant (HbS) that promotes distortion and early destruction of red blood cells, resulting in hemolytic anemia, vaso-occlusive crisis, ischemia and, ultimately, tissue damage. Hepatic function is specially compromised in SCD patients; however, the underlying pathological mechanisms remain largely unknown. In the current study, we confirmed the presence of hepatic damage in a murine model of SCD and, through a label free quantitative proteomic approach, we identified significant alterations in protein expression compared to healthy controls. These changes unveiled distinct proteome expression profiles between groups, with molecular alterations linked to impaired hepatic function, anemia, mitochondrial dysfunction, and alteration in lipid metabolism. We also confirmed these novel alterations through molecular and functional analyses, revealing a previously undescribed liver energy homeostasis imbalance, accompanied by accumulation of foam cells. Our findings provide new insights into the complex mechanisms underlying liver disease and potential therapeutic targets in SCD.
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