Biology subjects

Murphy, A. C.

Publications and source records attributed to Murphy, A. C..

3 recordsLinked to original sources

bioRxiv2025

Metabolomic, Lipidomic, and Enterohormone Changes in the Progression from MASLD to MASH

Background & AimsMetabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) and Metabolic Dysfunction-Associated Steatohepatitis (MASH) represent progressive stages of liver disease, with distinct metabolic and cellular alterations. This study investigates the progression from MASLD to MASH through metabolomics, lipidomics, and assessment of hormones. MethodsMale C57BL/6NTac mice were fed a high-fat diet for 16 weeks to induce MASLD and for 29 weeks to develop MASH. Aged-matched controls on a normal diet were used for comparison. Histology confirmed the progression of MASLD to MASH. We performed metabolomic and lipidomic profiling of liver, colon, and stool samples to identify metabolic and lipid alterations. Plasma enteroendocrine hormones and cytokines were quantified. Immunofluorescence was performed to assess enteroendocrine cells changes in the colon and the association of serotonin (5-HT) with fibronectin in the liver. ResultsMetabolomic and lipidomic analysis revealed significant alterations at different stages of the disease. Specifically, cholic acid was increased across the liver, colon, and stool in both MASLD and MASH mice compared to controls. Compared to the control group, MASLD mice exhibited an increase in enteroendocrine hormones, GLP-1, GIP, and PYY, whereas no changes were observed in MASH mice. Comparing MASLD to MASH livers, we found hepatic 5-HT levels were increased in MASH mice compared to MASLD mice. The MASH liver also exhibited a colocalization between fibronectin and 5-HT, suggesting a potential role of 5-HT in liver fibrosis. ConclusionsOur study provides novel insights into the progressive metabolic and hormonal changes from MASLD to MASH. The increase in cholic acid and differential enteroendocrine hormone responses highlight the complex interactions between the gut and liver in metabolic liver diseases. These findings suggest that enteroendocrine hormones may play a role in the progression of MASLD to MASH as well as liver fibrosis, offering potential therapeutic avenues for targeting the gut-liver axis in metabolic liver diseases.

cell biology↗

bioRxiv2024

Systemic inhibition of de novo purine biosynthesis prevents weight gain and improves metabolic health by increasing thermogenesis and decreasing food intake

ObjectiveObesity is a major health concern, largely because it contributes to type 2 diabetes mellitus (T2DM), cardiovascular disease, and various malignancies. Increase in circulating amino acids and lipids, in part due to adipose dysfunction, have been shown to drive obesity-mediated diseases. Similarly, elevated purines and uric acid, a degradation product of purine metabolism, are found in the bloodstream and in adipose tissue. These metabolic changes are correlated with metabolic syndrome, but little is known about the physiological effects of targeting purine biosynthesis. MethodsTo determine the effects of purine biosynthesis on organismal health we treated mice with mizoribine, an inhibitor of inosine monophosphate dehydrogenase 1 and 2 (IMPDH1/2), key enzymes in this pathway. Mice were fed either a low-fat (LFD; 13.5% kcal from fat) or a high-fat (HFD; 60% kcal from fat) diet for 30 days during drug or vehicle treatment. We ascertained the effects of mizoribine on weight gain, body composition, food intake and absorption, energy expenditure, and overall metabolic health. ResultsMizoribine treatment prevented mice on a HFD from gaining weight, but had no effect on mice on a LFD. Body composition analysis demonstrated that mizoribine significantly reduced fat mass but did not affect lean mass. Although mizoribine had no effect on lipid absorption, food intake was reduced. Furthermore, mizoribine treatment induced adaptive thermogenesis in skeletal muscle by upregulating sarcolipin, a regulator of muscle thermogenesis. While mizoribine-treated mice exhibited less adipose tissue than controls, we did not observe lipotoxicity. Rather, mizoribine-treated mice displayed improved glucose tolerance and reduced ectopic lipid accumulation. ConclusionsInhibiting purine biosynthesis prevents mice on a HFD from gaining weight, and improves their metabolic health, to a significant degree. We also demonstrated that the purine biosynthesis pathway plays a previously unknown role in skeletal muscle thermogenesis. A deeper mechanistic understanding of how purine biosynthesis promotes thermogenesis and decreases food intake may pave the way to new anti-obesity therapies. Crucially, given that many purine inhibitors have been FDA-approved for use in treating various conditions, our results indicate that they may benefit overweight or obese patients. HighlightsO_LIA purine biosynthesis inhibitor, mizoribine, protects against diet-induced weight gain C_LIO_LIMizoribine prevents fat mass gain in high-fat diet-fed male mice C_LIO_LIMizoribine reduces food intake and increases thermogenesis C_LIO_LIMizoribine induces expression of sarcolipin, a regulator of thermogenesis C_LIO_LIMizoribine treatment reduces ectopic lipids and increases glucose tolerance C_LI

physiology↗

bioRxiv2024

MICOS Complex Loss Governs Age-Associated Murine Mitochondrial Architecture and Metabolism in the Liver, While Sam50 Dictates Diet Changes

Background & AimsAging is associated with a significant decline in mitochondrial function in the liver, leading to an increased risk of liver disease. This study examines age-related changes in the mitochondrial structure of human and murine livers using a combination of Serial Block-Face Scanning Electron Microscopy (SBF-SEM) and mass spectrometry approaches. MethodsThis study integrates mitochondrial structure analysis in a murine model with an analysis of liver architecture, lipogenesis, and genetically regulated gene expression in human cohorts. We explored the Mitochondrial Contact Site and Cristae Organizing System (MICOS) complex using SBF-SEM, three-dimensional reconstruction with Amira software, and mass spectrometry techniques. ResultsAging leads to a reduction in mitochondrial size and complexity, resulting in changes in the metabolomic and lipidomic profiles of murine liver cells that are comparable to those observed in aged human samples. We find that genetically modeled expression of MICOS complex genes OPA1 and CHCHD3 is associated with chronic liver disease phenotypes within a large biobank population. Furthermore, we observed dysregulated mitochondrial calcium handling and increased oxidative stress due to the disruption of the MICOS complex. ConclusionOur study highlights the age-associated decline in mitochondrial complexity and metabolic regulation within the aging murine liver and the human population. We have identified that these changes are partially attributable to the age-related loss of the MICOS complex. Impact and implicationsThis study offers new insights into the changes to mitochondrial ultrastructure that occur during aging. Using SBF-SEM, the quantification of young and aged murine mitochondrial structure was performed, which had previously been an underexplored avenue for measuring mitochondrial changes. The discovery of mitochondrial ultrastructural changes, in conjunction with measurements of age-associated metabolic alterations and gene association data, provides a model for how changes in MICOS expression may modulate age-related impairment of hepatic mitochondria. These results provide a new model by which changes in MICOS protein expression may both cause and be a potential therapeutic target for age-related impairment in hepatic function. HighlightsDecreased modeled expression of CHCHD3 in individuals of European genetic ancestry is linked to liver transplant and cirrhosis, while decreased modeled expression of OPA1 in individuals of African genetic ancestry is associated with chronic liver disease and cirrhosis. Aging alters liver lipid accumulation, MICOS mRNA levels, and disease markers. Aging reduces the volume and complexity of murine liver ultrastructure. Aging and diet significantly alter the MICOS complex in mice. Knockdown of Mic60 and Chchd6 lowers Ca2+ uptake, retention, and induces oxidative stress in HepG2 cells. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=139 SRC="FIGDIR/small/599846v3_ufig1.gif" ALT="Figure 1000"> View larger version (47K): org.highwire.dtl.DTLVardef@1cdd61corg.highwire.dtl.DTLVardef@a3fb74org.highwire.dtl.DTLVardef@1d1ad36org.highwire.dtl.DTLVardef@c2e55f_HPS_FORMAT_FIGEXP M_FIG C_FIG Liver aging causes metabolic, lipidomic, and mitochondrial structural alterations, reflecting age-dependent losses in the MICOS complex. Key components of the MICOS complex (MIC60, CHCHD3 and CHCHD6) are illustrated.

physiology↗