Effects of apolipoprotein H downregulation on lipid metabolism, fatty liver disease, and gut microbiota dysbiosis.

Apolipoprotein H (APOH) downregulation can cause hepatic steatosis and gut microbiota dysbiosis. However, the mechanism by which APOH-regulated lipid metabolism contributes to metabolic dysfunction-associated steatotic liver disease (MASLD) remains undetermined. Herein, we aim to explore the regulatory effect of APOH, mediated through various pathways, on metabolic homeostasis and MASLD pathogenesis. We analyzed serum marker levels, liver histopathology, and cholesterol metabolism-related gene expression in global ApoH-/- C57BL/6 male mice. We used RNA sequencing and metabolomic techniques to investigate the association between liver metabolism and bacterial composition. Fifty-two differentially expressed genes were identified between ApoH-/- and WT mice. The mRNA levels of de novo lipogenesis genes were highly upregulated in ApoH-/- mice than in WT mice. Fatty acid, glycerophospholipid, sterol lipid, and triglyceride levels were elevated, while hyodeoxycholic acid levels were significantly reduced in the liver tissues of ApoH-/- mice than in those of WT mice. Microbial beta diversity was lower in ApoH-/- mice than in WT mice, and gut microbiota metabolic functions were activated in ApoH-/- mice. Moreover, ApoH transcripts were downregulated in patients with MASLD, and APOH-related differential genes were enriched in lipid metabolism. Open-source transcript-level data from human metabolic dysfunction-associated steatohepatitis livers reinforced a significant association between metabolic dysfunction-associated steatohepatitis and APOH downregulation. In conclusion, our studies demonstrated that APOH downregulation aggravates fatty liver and induces gut microbiota dysbiosis by dysregulating bile acids. Our findings offer a novel perspective on APOH-mediated lipid metabolic dysbiosis and provide a valuable framework for deciphering the role of APOH in fatty liver disease.

NF-κB p65 regulates hepatic lipogenesis by promoting nuclear entry of ChREBP in response to a high carbohydrate diet.

Overconsumption of sucrose and other sugars has been associated with nonalcoholic fatty liver disease (NAFLD). Reports suggest hepatic de novo lipogenesis (DNL) as an important contributor to and regulator of carbohydrate-induced hepatic lipid accumulation in NAFLD. The mechanisms responsible for the increase in hepatic DNL due to overconsumption of carbohydrate diet are less than clear; however, literatures suggest high carbohydrate diet to activate the lipogenic transcription factor carbohydrate response element-binding protein (ChREBP), which further transcribes genes involved in DNL. Here, we provide an evidence of an unknown link between nuclear factor kappa-light chain enhancer of activated B cells (NF-κB) activation and increased DNL. Our data indicates high carbohydrate diet to enforce nuclear shuttling of hepatic NF-κB p65 and repress transcript levels of sorcin, a cytosolic interacting partner of ChREBP. Reduced sorcin levels, further prompted ChREBP nuclear translocation, leading to enhanced DNL and intrahepatic lipid accumulation both in vivo and in vitro. We further report that pharmacological inhibition of NF-κB abrogated high carbohydrate diet-mediated sorcin repression and thereby prevented ChREBP nuclear translocation and this, in turn, attenuated hepatic lipid accumulation both in in vitro and in vivo. Additionally, sorcin knockdown blunted the lipid-lowering ability of the NF-κB inhibitor in vitro. Together, these data suggest a heretofore unknown role for NF-κB in regulating ChREBP nuclear localization and activation, in response to high carbohydrate diet, for further explorations in lines of NAFLD therapeutics.

Zinc oxide nanoparticles attenuate hepatic steatosis development in high-fat-diet fed mice through activated AMPK signaling axis.

Insulin resistance is thought to be a common link between obesity and Non-Alcoholic Fatty Liver Disease (NAFLD). NAFLD has now reached epidemic status worldwide and identification of molecules or pathways as newer therapeutic strategies either to prevent or overcome insulin resistance seems critical. Dysregulated hepatic lipogenesis (DNL) is a hallmark of NAFLD in humans and rodents. Therefore, reducing DNL accretion may be critical in the development of therapeutics of NAFLD. In our in vivo model (high-fat-diet fed [HFD] obese mice) we found Zinc oxide nanoparticles (ZnO NPs) significantly decreased HFD-induced hepatic steatosis and peripheral insulin resistance. This protective mechanism of ZnO NPs was signaled through hepatic SIRT1-LKB1-AMPK which restricted SREBP-1c within the cytosol limiting its transcriptional ability and thereby ameliorating HFD mediated DNL. These observations indicate that ZnO NP can serve as a therapeutic strategy to improve the physiological homeostasis during obesity and its associated metabolic abnormalities.

Renal Clearable New NIR Probe: Precise Quantification of Albumin in Biofluids and Fatty Liver Disease State Identification through Tissue Specific High Contrast Imaging in Vivo.

Development of a highly photostable, renal clearable, and nontoxic new NIR probe (CyG) for precise quantification of albumin in different biofluids and liver targeted in vivo albumin visualization is demonstrated. CyG's inherent property to interact selectively with albumin among different biomolecules in intracellular environment with high degree of sensitivity helps CyG in targeted liver imaging. In addition to its long excitation/emission wavelengths (λex = 740 nm, λem = 804 nm), which are much above the biological tissue opaque window (400-700 nm) ensuring better photon penetration, diminished tissue autofluorescence and high contrasts, its molecular mass and size are far below the renal cutoff and hence, CyG qualifies as imaging material for clinical studies. We anticipate that CyG will provide new strategies to overcome the pitfall of present day albumin detection methods as well as accelerate the detection process at relatively lower costs without compromising the accuracy of detection. Moreover, the renal excretion kinetic and intrahepatic albumin binding affinity of CyG can further be used to differentiate between fatty liver from healthy liver in an experimentally arrived mouse model using noninvasive technique.

Macrophage RAGE activation is proinflammatory in NASH.

Intrahepatic macrophages in nonalcoholic steatohepatitis (NASH) are heterogenous and include proinflammatory recruited monocyte-derived macrophages. The receptor for advanced glycation endproducts (RAGE) is expressed on macrophages and can be activated by damage associated molecular patterns (DAMPs) upregulated in NASH, yet the role of macrophage-specific RAGE signaling in NASH is unclear. Therefore, we hypothesized that RAGE-expressing macrophages are proinflammatory and mediate liver inflammation in NASH. Compared with healthy controls, RAGE expression was increased in liver biopsies from patients with NASH. In a high-fat, -fructose, and -cholesterol-induced (FFC)-induced murine model of NASH, RAGE expression was increased, specifically on recruited macrophages. FFC mice that received a pharmacological inhibitor of RAGE (TTP488), and myeloid-specific RAGE KO mice (RAGE-MKO) had attenuated liver injury associated with a reduced accumulation of RAGE+ recruited macrophages. Transcriptomics analysis suggested that pathways of macrophage and T cell activation were upregulated by FFC diet, inhibited by TTP488 treatment, and reduced in RAGE-MKO mice. Correspondingly, the secretome of ligand-stimulated BM-derived macrophages from RAGE-MKO mice had an attenuated capacity to activate CD8+ T cells. Our data implicate RAGE as what we propose to be a novel and potentially targetable mediator of the proinflammatory signaling of recruited macrophages in NASH.

Molecular pathways dysregulated by Pb2+ exposure prompts pancreatic beta-cell dysfunction.

Type 2 diabetes mellitus (T2DM) is a metabolic disease characterized by reduced insulin sensitivity and dysfunction of ß-cells. Although the increasing prevalence of diabetes worldwide is largely attributed to genetic predisposition or lifestyle factors (insufficient physical activity), and caloric intake. Environmental factors, exposure to xenobiotics and heavy metals have also been reported to be causative factors of T2DM. At this juncture, we, through our work unveil a plausible link between Pb2+ exposure and diabetes mellitus, and delineated a comprehensive understanding of the potential mechanisms of Pb2+-induced ß-cells dysfunction. In our in vivo observations, we found that Pb2+ exposure strongly reduced glucose-stimulated insulin secretion and diminished functional pancreatic ß-cell mass. Mechanistically, we found that Pb2+ downregulates intracellular cAMP level via hyper-activating Ca2+/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1C and thereby reduces glucose-stimulated insulin secretion. Further, we report that Pb2+ inhibited mitochondrial adenosine triphosphate production and also identified Pb2+ as a negative regulator of ß-cell proliferation via Ca2+/calmodulin-dependent protein kinase kinases-pAMPK-pRaptor axis. Together, our findings strongly reinforce Pb2+ to hijack the physiological role of calcium ions, by mimicking Ca2+ within pancreatic ß-cell and thereby stands as a diabetogenic xenobiotic.

Liver-Derived S100A6 Propels ß-Cell Dysfunction in NAFLD.

Nonalcoholic fatty liver disease (NAFLD) is an independent predictor of systemic insulin resistance and type 2 diabetes mellitus (T2DM). However, converse correlates between excess liver fat content and ß-cell function remain equivocal. Specifically, how the accumulation of liver fat consequent to the enhanced de novo lipogenesis (DNL) leads to pancreatic ß-cell failure and eventually to T2DM is elusive. Here, we have identified that low-molecular-weight calcium-binding protein S100A6, or calcyclin, inhibits glucose-stimulated insulin secretion (GSIS) from ß cells through activation of the receptor for the advanced glycation end products and diminution of mitochondrial respiration. Serum S100A6 level is elevated both in human patients with NAFLD and in a high-fat diet-induced mouse model of NAFLD. Although serum S100A6 levels are negatively associated with ß-cell insulin secretory capacity in human patients, depletion of hepatic S100A6 improves GSIS and glycemia in mice, suggesting that S100A6 contributes to the pathophysiology of diabetes in NAFLD. Moreover, transcriptional induction of hepatic S100A6 is driven by the potent regulator of DNL, carbohydrate response element-binding protein (ChREBP), and ectopic expression of ChREBP in the liver suppresses GSIS in a S100A6-sensitive manner. Together, these data suggest elevated serum levels of S100A6 may serve as a biomarker in identifying patients with NAFLD with a heightened risk of developing ß-cell dysfunction. Overall, our data implicate S100A6 as, to our knowledge, a hitherto unknown hepatokine to be activated by ChREBP and that participates in the hepato-pancreatic communication to impair insulin secretion and drive the development of T2DM in NAFLD.

Causative and Sanative dynamicity of ChREBP in Hepato-Metabolic disorders.

ChREBP is the master regulator of carbohydrate dependent glycolytic and lipogenic flux within metabolic tissues. It plays a vital role in hyper-calorific milieu by activating glycolysis, lipogenesis along with pentose phosphate shunt and glycogen synthesis, fostering immediate reduction in the systemic glycemic levels. Liver being the primary organ to sense disproportionate dietary intake and linked physiological stress, stimulates ChREBP to perform the aforementioned processes. Activated ChREBP also inhibits lipolysis and encourages proper disposal of excessive triglycerides into adipocytes from the liver ablating hepatic intracellular lipid trafficking. Chronic overeating or onset of positive energy balance, hyper-activates ChREBP and signals development, intensification of hepato-metabolic disorders, and allied discrepancies in the whole-body metabolic functioning. ChREBP thus gets negatively connotated as the primary regulator of hepatic disorders, owing to its inherent features as the primary glycemic sensor and the only transcription factor that can transduce glucose-dependent glycolytic and lipogenic signals. Through this review, we - try to recapitulate and emphasize on the sanative events coordinated by ChREBP in several pathophysiological states. In totality, we aim to uncouple the disease-causing aspects of ChREBP from its positive attributes evoked during a metabolic crisis, in hepato-metabolic diseases.

A long-range emissive mega-Stokes inorganic-organic hybrid material with peripheral carboxyl functionality for As(v) recognition and its application in bioimaging.

We demonstrate a strategy for the recognition of As5+ in aqueous solution using a red-emissive probe based on a perylene-Cu2+ ensemble decorated with peripheral free carboxyl functionality. Single crystal analysis helped us to understand the chemical structure of the probe. To the best of our knowledge, this is the first probe for arsenic detection which emits in the red region (λem = 600 nm). The perylene-Cu2+ ensemble exhibited a mega-Stokes shift (>100 nm) with a high degree of selectivity upon interaction with As5+, which indicated that the present probe has the potential to be used as a turn-on optical sensor for selective detection of As5+ with fewer experimental limitations. The detection limit was found to be 26 nM. Inspired by its good emissive properties, the ensemble was further explored for imaging As5+ in live cells. Because of its long-range emissive nature, no autofluorescence from the cellular species was observed during the imaging process. The probe was evaluated to be non-toxic and successfully permeated the cell membrane without the help of any permeabilizing agent to image As5+.