breath-collection-from-children-for-disease-biomarker-discovery

Breath Collection from Children for Disease Biomarker Discovery

Breath collection and analysis can be used to discover volatile biomarkers in a number of infectious and non-infectious diseases, such as malaria, ...

Washington University School of Medicine

The macroautophagy/autophagy-inducing disaccharide, trehalose, has been proposed to be a promising therapeutic agent against neurodegenerative and cardiometabolic diseases. We recently showed that trehalose attenuates hepatic steatosis in part by blocking hepatocyte glucose transport to induce hepatocyte autophagic flux. However, although every major demonstration of trehalose action invokes activating autophagic flux as its primary function, the mechanism of action of trehalose in whole-body energy metabolism remains poorly defined. Here, we demonstrate that trehalose induces hepatocyte TFEB (transcription factor EB)-dependent thermogenesis in vivo, concomitant with upregulation of hepatic and white adipose expression of UCP1 (uncoupling protein 1 [mitochondrial, protein carrier]). Mechanistically, we provide evidence that hepatocyte fasting transcriptional and metabolic responses depend upon PPARGC1A (peroxisome proliferative activated receptor, gamma, coactivator 1 alpha), TFEB, and FGF21 (fibroblast growth factor 21) signaling. Strikingly, hepatocyte-selective TFEB knockdown abrogated trehalose induction of thermogenesis and white adipose tissue UCP1 upregulation in vivo. In contrast, we found that trehalose action on thermogenesis was independent of LEP (leptin) and the autophagy pathway, as there was robust thermogenic induction in trehalose-treated ob/ob, Becn1, Atg16l1, and Epg5 mutant mice. We conclude that trehalose induces metabolically favorable effects on whole-body thermogenesis in part via hepatocyte-centered fasting-like mechanisms that appear to be independent of autophagic flux. Our findings elucidate a novel mechanism by which trehalose acts as a metabolic therapeutic agent by activating hepatic fasting responses. More broadly, the hepatic glucose fasting response may be of clinical utility against overnutrition-driven disease, such as obesity and type 2 diabetes mellitus.

TFEB-dependent induction of thermogenesis by the hepatocyte SLC2A inhibitor trehalose.

The hepatic glucose fasting response is gaining traction as a therapeutic pathway to enhance hepatic and whole-host metabolism. However, the mechanisms underlying these metabolic effects remain unclear. Here, we demonstrate the epidermal-type lipoxygenase, eLOX3 (encoded by its gene, Aloxe3), is a potentially novel effector of the therapeutic fasting response. We show that Aloxe3 is activated during fasting, glucose withdrawal, or trehalose/trehalose analogue treatment. Hepatocyte-specific Aloxe3 expression reduced weight gain and hepatic steatosis in diet-induced and genetically obese (db/db) mouse models. Aloxe3 expression, moreover, enhanced basal thermogenesis and abrogated insulin resistance in db/db diabetic mice. Targeted metabolomics demonstrated accumulation of the PPARγ ligand 12-KETE in hepatocytes overexpressing Aloxe3. Strikingly, PPARγ inhibition reversed hepatic Aloxe3-mediated insulin sensitization, suppression of hepatocellular ATP production and oxygen consumption, and gene induction of PPARγ coactivator-1α (PGC1α) expression. Moreover, hepatocyte-specific PPARγ deletion reversed the therapeutic effect of hepatic Aloxe3 expression on diet-induced insulin intolerance. Aloxe3 is, therefore, a potentially novel effector of the hepatocellular fasting response that leverages both PPARγ-mediated and pleiotropic effects to augment hepatic and whole-host metabolism, and it is, thus, a promising target to ameliorate metabolic disease.

Hepatocyte ALOXE3 is induced during adaptive fasting and enhances insulin sensitivity by activating hepatic PPARγ.

Iron is a critical nutrient required by hosts and pathogens. Uropathogenic Escherichia coli (UPEC), the principal causative agent of urinary tract infections (UTIs), chelate iron for their survival and persistence. Here, we demonstrate that dietary modulation of iron availability limits UPEC burden in a mouse model of UTI. Mice on a low iron diet exhibit reduced systemic and bladder mucosal iron availability, harbor significantly lower bacterial burden, concomitant with dampened inflammation. Hepcidin is a master regulator of iron that controls iron-dependent UPEC intracellular growth. Hepcidin deficient mice ( Hamp1 ) exhibit accumulation of iron deposits, persistent bacterial burden in the bladder, and a heightened inflammatory response to UTI. However, a low iron dietary regimen reverses the iron overload and increased bacterial burden phenotypes in Hamp1 mice. Thus, modulation of iron levels via diet can reduce UPEC infection and persistence, which may have significant implications for clinical management of UTI.

Brian DeBosch

Department of Pediatrics,
Cell Biology & Physiology

Washington University School of Medicine

Breath Collection from Children for Disease Biomarker Discovery

Brian DeBosch

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Department of Pediatrics,Cell Biology & Physiology

Washington University School of Medicine

Breath Collection from Children for Disease Biomarker Discovery

Department of Pediatrics,
Cell Biology & Physiology