Biology subjects

Hill, B. G.

Publications and source records attributed to Hill, B. G..

4 recordsLinked to original sources

bioRxiv2026

Dietary fructose promotes MASH/HCC progression through enhanced intestinal HIF-2α-dependent iron absorption

Dietary fructose is a major risk factor driving the progression of metabolic dysfunction-associated steatohepatitis (MASH) and hepatocellular carcinoma (HCC). However, the underlying fructose-induced nutrient-sensing pathway remains unclear. Here, we report that fructose facilitates iron absorption through the (Ketohexokinase) KHK/PKM2/HIF-2 axis, driving MASH and HCC development. Fructose aberrantly stabilizes intestinal HIF-; this effect is abrogated by a KHK inhibitor and genetic Khk deletion. Mechanistically, fructose-induced metabolic reprogramming drives glutamine-dependent oxidative phosphorylation, leading to HIF- stabilization, which is mediated by pyruvate kinase M2 (PKM2). A selective PKM2 inhibitor rescues reduced intestinal HIF- stability in Khk-deficient mice. Furthermore, dietary fructose increases plasma iron levels. Conversely, Khk-deficient mice exhibit spontaneous systemic iron deficiency, characterized by hypochromic anemia. Moreover, Khk deficiency inhibits iron absorption in a HIF-2-dependent manner. Finally, fructose promotes MASH and HCC progression in an iron-dependent manner. This study reveals a unique, therapeutically targetable nutrient-sensing pathway utilized by dietary fructose. In briefMitchell et al. demonstrate that fructose consumption increases plasma iron levels, while KHK deficiency inhibits iron absorption in a HIF-2-dependent manner. Mechanistically, dietary fructose-induced metabolic reprogramming aberrantly stabilizes intestinal HIF-, which is mediated by PKM2. Fructose promotes MASH and HCC progression in an iron-dependent manner. HighlightsO_LIFructose aberrantly stabilizes intestinal HIF- C_LIO_LIKHK is required for intestinal HIF- stability C_LIO_LIKHK deficiency inhibits iron absorption in a HIF-2-dependent manner C_LIO_LIDietary fructose promotes MASH and HCC progression in an iron-dependent manner C_LI

physiology↗

bioRxiv2024

Exercise-stimulated Resolvin Biosynthesis in Adipose Tissue is Abrogated by High Fat Diet-induced Adrenergic Deficiency

ObjectiveDiet-induced white adipose tissue inflammation is associated with insulin resistance and metabolic perturbations. Conversely, exercise (Exe) protects against the development of chronic inflammation and insulin resistance independent of changes in weight; however, the mechanisms remain largely unknown. We have recently shown that, through adrenergic stimulation of macrophages, exercise promotes resolution of acute peritoneal inflammation by enhancing the biosynthesis of specialized pro-resolving lipid mediators (SPMs). In this study, we sought to determine if exercise stimulates pro-resolving pathways in adipose tissue and whether this response is modified by diet. Specifically, we hypothesized that high fat diet feeding disrupts exercise-stimulated resolution by inhibiting adrenergic signaling, priming the development of chronic inflammation in adipose tissue (AT). Approach and ResultsTo explore the dietary dependence of the pro-resolving effects of Exe, mice were fed either a control or high-fat diet (HFD) for 2 weeks prior to, and throughout, a 4 wk period of daily treadmill running. Glucose handling, body weight and composition, and exercise performance were evaluated at the end of the feeding and exercise interventions. Likewise, catecholamines and their biosynthetic enzymes were measured along with AT SPM biosynthesis and macrophage phenotype and abundance. When compared with sedentary controls (Sed), macrophages isolated from mice exposed to 4 wk of exercise display elevated expression of the SPM biosynthetic enzyme Alox15, while whole AT SPM levels and anti-inflammatory CD301+ M2 macrophages increased. These changes were dependent upon diet as 6 wk of feeding with HFD abrogated the pro-resolving effect of exercise when compared with control diet-fed animals. Interestingly, exercise-induced epinephrine production was inhibited by HFD, which diminished expression of the epinephrine biosynthetic enzyme phenylethanolamine N-methyltransferase (PNMT) in adrenal glands. ConclusionTaken together, these results suggest that a diet high in fat diminishes the pro-resolving effects of exercise in adipose tissue via decreasing the biosynthesis of catecholamines. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=192 SRC="FIGDIR/small/608014v1_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@1b508e7org.highwire.dtl.DTLVardef@5b9d8corg.highwire.dtl.DTLVardef@c46707org.highwire.dtl.DTLVardef@48083e_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2024

Dietary Branched Chain Amino Acids Modify Post-Infarct Cardiac Remodeling and Function in the Murine Heart

IntroductionBranch-chain amino acids (BCAA) are markedly elevated in the heart following myocardial infarction (MI) in both humans and animal models. Nevertheless, it remains unclear whether dietary BCAA levels influence post-MI remodeling. We hypothesize that lowering dietary BCAA levels prevents adverse cardiac remodeling after MI. Methods and ResultsTo assess whether altering dietary BCAA levels would impact circulating BCAA concentrations, mice were fed a low (1/3x), normal (1x), or high (2x) BCAA diet over a 7-day period. We found that mice fed the low BCAA diet had >2-fold lower circulating BCAA concentrations when compared with normal and high BCAA diet feeding strategies; notably, the high BCAA diet did not further increase BCAA levels over the normal chow diet. To investigate the impact of dietary BCAAs on cardiac remodeling and function after MI, male and female mice were fed either the low or high BCAA diet for 2 wk prior to MI and for 4 wk after MI. Although body weights or heart masses were not different in female mice fed the custom diets, male mice fed the high BCAA diet had significantly higher body and heart masses than those on the low BCAA diet. Echocardiographic assessments revealed that the low BCAA diet preserved stroke volume and cardiac output for the duration of the study, while the high BCAA diet led to progressive decreases in cardiac function. Although no discernible differences in cardiac fibrosis, scar collagen topography, or cardiomyocyte cross-sectional area were found between the dietary groups, male mice fed the high BCAA diet showed longer cardiomyocytes and higher capillary density compared with the low BCAA group. ConclusionsProvision of a diet low in BCAAs to mice mitigates eccentric cardiomyocyte remodeling and loss of cardiac function after MI, with dietary effects more prominent in males.

physiology↗

bioRxiv2020

Heart Slice Culture System Reliably Demonstrates Clinical Drug-Related Cardiotoxicity

The limited availability of human heart tissue and its complex cell composition are major limiting factors for reliable testing drug efficacy, toxicity and understanding mechanism. Recently, we developed a functional human and pig heart slice biomimetic culture system that fully preserves the viability and functionality of 300 {micro}m heart slices for 6 days. Here, we tested the reliability of this culture system in delineating the mechanisms of known anti-cancer drugs that cause cardiomyopathy. We tested three anti-cancer drugs (doxorubicin, trastuzumab, and sunitinib) associated with different mechanisms leading to cardiotoxicity at three concentrations and assessed the effect of these drugs on heart slice viability, structure, function and transcriptome. Slices incubated with any of these drugs for 48 h showed significant loss in viability, cardiomyocyte structure and functionality. Mechanistically, RNA sequencing demonstrated a significant downregulation of cardiac genes and upregulation of oxidative response in doxorubicin-treated tissues. Trastuzumab treatment caused major downregulation in cardiac muscle contraction-related genes, consistent with its clinically known direct effect on cardiomyocytes. Interestingly, sunitinib treatment resulted in significant downregulation of angiogenesis-related genes in line with its mechanism of action. Heart slices are not only able to demonstrate the expected toxicity of doxorubicin and trastuzumab similar to hiPS-derived-cardiomyocytes; they are superior in detecting sunitinib cardiotoxicity phenotypes and mechanism in the clinically relevant concentration range, 100 nM - 1 {micro}M. These results indicate that heart slice tissue culture models have the potential to become a reliable platform for testing drug toxicity and mechanism of action.

cell biology↗