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Nonalcoholic fatty liver disease (NAFLD) is characterized by excess lipid accumulation that can progress to inflammation (nonalcoholic steatohepatitis, NASH), and fibrosis. Serum β-hydroxybutyrate (β-HB), a product of the ketogenic pathway, is commonly used as a surrogate marker for hepatic fatty acid oxidation (FAO). However, it remains uncertain whether this relationship holds true in the context of NAFLD in humans. We compared fasting serum β-HB levels with direct measurement of liver mitochondrial palmitate oxidation in humans stratified based on NAFLD severity ( n = 142). Patients were stratified based on NAFLD activity score (NAS): NAS = 0 (no disease), NAS = 1-2 (mild), NAS = 3-4 (moderate), and NAS ≥ 5 (advanced). Moderate and advanced NAFLD is associated with reductions in liver 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), serum β-HB, but not 3-hydroxy-3-methylglutaryl-CoA lyase (HMGCL) mRNA, relative to no disease. Worsening liver mitochondrial complete palmitate oxidation corresponded with lower H MGCS2 mRNA but not total (complete + incomplete) palmitate oxidation. Interestingly, we found that liver HMGCS2 mRNA and serum β-HB correlated with liver mitochondrial β-hydroxyacyl-CoA dehydrogenase (β-HAD) activity and CPT1A mRNA. Also, lower mitochondrial mass and markers of mitochondrial turnover positively correlated with lower HMGCS2 in the liver. These data suggest that liver ketogenesis and FAO occur at comparable rates in individuals with NAFLD. Our findings support the utility of serum β-HB to serve as a marker of liver injury and hepatic FAO in the context of NAFLD. NEW & NOTEWORTHY Serum β-hydroxybutyrate (β-HB) is frequently utilized as a surrogate marker for hepatic fatty acid oxidation; however, few studies have investigated this relationship during states of liver disease. We found that the progression of nonalcoholic fatty liver disease (NAFLD) is associated with reductions in circulating β-HB and liver 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2). As well, decreased rates of hepatic fatty acid oxidation correlated with liver HMGCS2 mRNA and serum β-HB. Our work supports serum β-HB as a potential marker for hepatic fatty acid oxidation and liver injury during NAFLD.

Emerging evidence suggests that intestinal microbes regulate host physiology and cardiometabolic health, although the mechanism(s) by which they do so is unclear. Indoles are a group of compounds produced from bacterial metabolism of the amino acid tryptophan. In light of recent data suggesting broad physiological effects of indoles on host physiology, we examined whether indole-3-propionic acid (IPA) would protect mice from the cardiometabolic consequences of a Western diet. Male C57BL/6J mice were fed either a standard diet (SD) or Western diet (WD) for 5 mo and received normal autoclaved drinking water or water supplemented with IPA (0.1 mg/mL; SD + IPA and WD + IPA). WD feeding led to increased liver triglycerides and makers of inflammation, with no effect of IPA. At 5 mo, arterial stiffness was significantly higher in WD and WD + IPA compared with SD (WD: 485.7 ± 6.7 and WD + IPA: 492.8 ± 8.6 vs. SD: 436.9 ± 7.0 cm/s, P < 0.05) but not SD + IPA (SD + IPA: 468.1 ± 6.6 vs. WD groups, P > 0.05). Supplementation with IPA in the SD + IPA group significantly increased glucose AUC compared with SD mice (SD + IPA: 1,763.3 ± 92.0 vs. SD: 1,397.6 ± 64.0, P < 0.05), and no significant differences were observed among either the WD or WD + IPA groups (WD: 1,623.5 ± 77.3 and WD + IPA: 1,658.4 ± 88.4, P > 0.05). Gut microbiota changes were driven by WD feeding, whereas IPA supplementation drove differences in SD-fed mice. In conclusion, supplementation with IPA did not improve cardiometabolic outcomes in WD-fed mice and may have worsened some parameters in SD-fed mice, suggesting that IPA is not a critical signal mediating WD-induced cardiometabolic dysfunction downstream of the gut microbiota. NEW & NOTEWORTHY The gut microbiota has been shown to mediate host health. Emerging data implicate gut microbial metabolites of tryptophan metabolism as potential important mediators. We examined the effects of indole-3-propionic acid in Western diet-fed mice and found no beneficial cardiometabolic effects. Our data do not support the supposition that indole-3-propionic acid (IPA) mediates beneficial metabolic effects downstream of the gut microbiota and may be potentially deleterious in higher circulating levels.

Diabetic nephropathy (DN) is a serious complication of both type 1 and type 2 diabetes mellitus. The disease is now the most common cause of end-stage kidney disease (ESKD) in developed countries, and both the incidence and prevalence of diabetes mellitus is increasing worldwide. Current treatments are directed at controlling hyperglycemia and hypertension, as well as blockade of the renin angiotensin system with angiotensin-converting enzyme inhibitors (ACEIs), and angiotensin receptor blockers. Despite these therapies, DN progresses to ESKD in many patients. As a result, much interest is focused on developing new therapies. It has been over two decades since ACEIs were shown to have beneficial effects in DN independent of their blood pressure-lowering actions. Since that time, our understanding of disease mechanisms in DN has evolved. In this review, we summarize major cell signaling pathways implicated in the pathogenesis of diabetic kidney disease, as well as emerging treatment strategies. The goal is to identify promising targets that might be translated into therapies for the treatment of patients with diabetic kidney disease.

This investigation compared how hindlimb unweighting (HU) affected the contractile function of single soleus muscle fibers from 12- and 30-mo-old Fischer 344 Brown Norway F1 Hybrid rats. After 1 wk of HU, functional properties of single permeabilized fibers were studied, and, subsequently, the fiber type was established by myosin heavy chain (MHC) analysis. After HU, the relative mass of soleus declined by 12 and 19% and the relative mass of the gastrocnemius declined by 15 and 13% in 12- and 30-mo-old animals, respectively. In 12-mo-old animals, the peak active force (5.0 +/- 0.2 x10(-4) vs. 3.8 +/- 0.2 x10(-4) N) and the peak specific tension (92 +/- 4 vs. 78 +/- 3 kN/m2) were significantly reduced in the MHC type I fibers by 24 and 15%, respectively. In 30-mo-old animals, the peak active force declined by 40% (4.7 +/- 0.2 x10(-4) vs. 2.8 +/- 0. 3 x10(-4) N) and the peak specific tension declined by 30% (79 +/- 5 vs. 55 +/- 4 kN/m2). The maximal unloaded shortening velocity of the MHC type I fibers increased in 12-mo-old animals (from 1.65 +/- 0.12 to 2.59 +/- 0.26 fiber lengths/s) and in 30-mo-old animals (from 0.90 +/- 0. 09 to 1.50 +/- 0.10 fiber lengths/s) after HU. Collectively, these data suggest that the effects of HU on single soleus skeletal muscle fiber function occur in both age groups; however, the single MHC type I fibers from the older animals show greater changes than do single MHC type I fibers from younger animals.

The present study was designed to determine the value of nuclear magnetic resonance (NMR) imaging as a technique for quantifying lung water distribution and to estimate the degree of spatial resolution achieved by this technique. The spatial distribution of water was determined in six small (0.76 ml) rat lung tissue specimens by an NMR line-scan technique. After NMR imaging, each lung specimen was frozen and subdivided into slices; the gravimetric lung water content for each lung slice was compared with the integrated NMR water content over the volume corresponding to the same lung slice. In each tissue specimen, NMR and gravimetric lung water values were significantly correlated; the correlation coefficient for the pooled data for all six lung specimens was 0.91 (P less than 0.01). In two lung specimens, NMR values tended to be slightly higher than the gravimetric values. The magnitude of the difference between NMR and gravimetric values was generally less than 20% and only occasionally exceeded 25%. Our results suggest that the NMR-imaging method provides satisfactory estimates of lung water content and its distribution; the resolving power of the technique is excellent, as shown by its ability to detect water content differences between lung tissue slices of volume as small as 0.076 ml.

Inflated lung has a nuclear magnetic resonance (NMR) free-induction decay (FID) which is short compared with that of collapsed lung and those of other body tissues. An almost identically short FID is obtained from a slurry of 5-micron alumina particles in water. Interfaces between air and water in lung and between alumina and water in the slurry appear to be the source of spatial internal magnetic inhomogeneities which produce NMR line broadening and the short FID. Paired images that included lung, taken with paired symmetric and asymmetric NMR spin-echo sequences, permit the generation of an image, by subtraction, of the lung isolated from surrounding tissue. These new lung images are neither proton density, T1 (spin-lattice relaxation time), nor T2 (spin-spin relaxation time) images. They complement current NMR images and provide information about regional lung inflation. This previously unrecognized NMR property of lung tissue has potential application in NMR imaging, in quantitative determination of lung water and its distribution, and in the quantitation of regional lung inflation.

Lethal gas embolism always occurs after FC 80 liquid fluorocarbon is injected intravenously (0.1 ml/kg body mass) in dogs breathing room air but not in dogs breathing oxygenated FC 80 liquid fluorocarbon. Gas embolism is not prevented in dogs that have been injected intravenously with FC 80 when they are exposed to 2 ATA (atmospheres absolute) 20% 02-80% N2, 9 ATA 5% O2-95% He, or 1 ATA 100%, O2. In dogs that die of FC 80-induced gas embolism, free gas in the right atrium contains approximately 0.5 g FC 80/liter, and Po2 and Pco2 in the gas are in equilibrium with their corresponding tensions in right atrial blood. These observations are consistent with the hypothesis that PFC 80 in alveolar gas does not equilibrate with PFC 80 (55 mmHg) in blood. The total gas tension in pulmonary capillary blood containing FC 80 and its vapor thus exceeds the total tension of alveolar gases (atmospheric pressure). Bubbles of O2, CO2, N2, FC 80, and water vapor form in the regions of the pulmonary capillary bed where the total tension of gases dissolved in blood exceeds the absolute blood pressure.