Metabolic responses to albumin deficiency differ distinctly between partial and full ablation of albumin expression in mice.

It had been observed that homozygous albumin knockout mice (Alb-/-) exhibit low plasma free fatty acid (FFA) concentration and improved blood glucose regulation. However, it was not yet known to what extent heterozygous albumin knockout (Alb+/-) mice would display a similar phenotype. Alb-/-, Alb+/-, and wild-type (WT) female mice were studied on a low-fat diet (LFD) or high-fat diet (HFD). On both diets, decreased plasma FFA concentration, and improved glucose tolerance test were observed in Alb-/-, but not in Alb+/-, compared to WT. Plasma adiponectin concentration showed greater elevation in Alb-/- than Alb+/-. Consistent with that, adiponectin gene expression was significantly higher in Alb-/- mice than in Alb+/- and WT mice. A dose-dependent response was observed for hepatic Acadl gene expression showing higher Acadl gene expression in Alb-/- mice than in Alb+/- and WT mice. In conclusion, although female Alb+/- mice exhibited some slight differences from WT mice (e.g., increased plasma adiponectin and hepatic Acadl gene expression), Alb+/- mice did not exhibit improved glucoregulation in comparison to WT mice, indicating that a minor suppression of albumin expression is not sufficient to improve glucoregulation. Furthermore, it is now clear that although the response of female mice to HFD might be unique from how males generally respond, still the complete albumin deficiency in Alb-/- mice and the associated FFA reduction is capable of improving glucoregulation in females on this diet. The present results have implications for the role of albumin and FFA in the regulation of metabolism.

Combining albumin deficiency and acute exercise reduces hepatic lipid droplet size in mice.

Hepatic lipid droplets (LDs) are implicated in ectopic lipid accumulation. The core of LDs, triacylglycerol (TAG), is synthesized from the esterification of fatty acids to a glycerol-3-phosphate (G-3-P) backbone. Albumin transports plasma free fatty acids, and previously albumin knockout (Alb-/-) mice were shown to exhibit lower hepatic TAG levels than wildtype (WT). Exercise is a beneficial strategy to alter hepatic metabolism, but its impacts on reducing hepatic lipids are far from satisfactory. The aim of this study was to investigate the combined effect of albumin deficiency and acute exercise on hepatic LDs. Eight-week-old male Alb-/- and WT mice were divided into sedentary and exercise groups. Exercised mice performed a 30-min high-intensity exercise bout. Results showed that sedentary Alb-/- mice had smaller hepatic LDs (P < 0.0001), associated with mitochondria, while WT mice exhibited larger LDs, surrounded by glycogen granules. Following acute exercise, hepatic LDs in Alb-/- mice reduced by 40% in size, while in WT increased by 14% (P < 0.0001). The maintenance of WT hepatic LDs was associated with elevated G-3-P level (P < 0.05), potentially derived from glycogen (R = -0.32, %change in glycogen versus LD content, P < 0.05). The reduction in Alb-/- mice LDs after exercise was possibly due to their low glycogen level. In conclusion, Alb-/- mice exhibited an enhanced capacity for reducing hepatic LD size and content in response to exercise. These findings suggest that modulating albumin's functions combined with exercise could be a potential strategy to reduce ectopic lipid deposition in the liver.

Muscle metabolic reprogramming underlies the resistance of liver fatty acid-binding protein (LFABP)-null mice to high-fat feeding-induced decline in exercise capacity.

Liver fatty acid-binding protein (LFABP) binds long-chain fatty acids with high affinity and is abundantly expressed in the liver and small intestine. Although LFABP is thought to function in intracellular lipid trafficking, studies of LFABP-null (LFABP-/-) mice have also indicated a role in regulating systemic energy homeostasis. We and others have reported that LFABP-/- mice become more obese than wildtype (WT) mice upon high-fat feeding. Here, we show that despite increased body weight and fat mass, LFABP-/- mice are protected from a high-fat feeding-induced decline in exercise capacity, displaying an approximate doubling of running distance compared with WT mice. To understand this surprising exercise phenotype, we focused on metabolic alterations in the skeletal muscle due to LFABP ablation. Compared with WT mice, resting skeletal muscle of LFABP-/- mice had higher glycogen and intramuscular triglyceride levels as well as an increased fatty acid oxidation rate and greater mitochondrial enzyme activities, suggesting higher substrate availability and substrate utilization capacity. Dynamic changes in the respiratory exchange ratio during exercise indicated that LFABP-/- mice use more carbohydrate in the beginning of an exercise period and then switch to using lipids preferentially in the later stage. Consistently, LFABP-/- mice exhibited a greater decrease in muscle glycogen stores during exercise and elevated circulating free fatty acid levels postexercise. We conclude that, because LFABP is not expressed in muscle, its ablation appears to promote interorgan signaling that alters muscle substrate levels and metabolism, thereby contributing to the prevention of high-fat feeding-induced skeletal muscle impairment.

Acute exercise in mice transiently remodels the hepatic lipidome in an intensity-dependent manner.

BACKGROUND: The content of triacylglycerol (TAG) in the liver is known to rapidly increase after a single bout of exercise followed by recovery to sedentary levels. The response of other hepatic lipids, and acyl chain composition of lipid classes, would provide a deeper understanding of the response of hepatic lipid metabolism to acute exercise. METHODS: Female mice performed a single bout of continuous exercise (CE), high-intensity interval exercise (HIIE), or no exercise (CON). The total content of various lipids in the liver, and fatty acids within lipid classes, were measured in tissues collected 3 h after exercise (Day 1) and the day following exercise (Day 2). RESULTS: The total concentration of TAG rose on Day 1 after exercise (P < 0.05), with a greater elevation in HIIE than CE (P < 0.05), followed by a decline toward CON levels on Day 2. The total concentration of other measured lipid classes was not significantly altered by exercise. However, n-6 polyunsaturated fatty acid relative abundance in diacylglycerol (DAG) was increased by HIIE (P < 0.05). In CON liver, TAG content was positively correlated with DAG and phosphatidylethanolamine (P < 0.05), while these statistical associations were disrupted in exercised mice on Day 1. CONCLUSIONS: The response of lipid metabolism to exercise involves the coordination of metabolism between various tissues, and the lipid metabolism response to acute exercise places a metabolic burden upon the liver. The present findings describe how the liver copes with this metabolic challenge. The flexibility of the TAG pool size in the liver, and other remodeling of the hepatic lipidome, may be fundamental components of the physiological response to intense exercise.

An unusual clinical presentation of myxoid dermatofibrosarcoma protuberans with a prominent vasculature: A potential pitfall in the diagnosis of myxoid soft tissue tumors.

Dermatofibrosarcoma protuberans (DFSP) is a rare soft tissue tumor that arises primarily on the trunk and extremities but seldom on the scalp. Several variants of DFSP have been described, including myxoid DFSP. Although typical DFSP may have focally myxoid areas, myxoid DFSP, in which most of the stroma is myxoid, is rare and can pose diagnostic challenges. Here, we report a case of myxoid DFSP with an unusual clinical presentation that could have been mistaken for a lipoma. Additionally, the myxoid DFSP displayed prominent vasculature in a myxoid stroma, which could have been mistaken for a myxoid liposarcoma.

Sexual dimorphism in the hepatic protein response to a moderate trans fat diet in senescence-accelerated mice.

BACKGROUND: Aging is characterized by increases in inflammation and oxidative stress, conditions that are exacerbated by environmental factors such as diet. In this study, we investigated the effects of a trans-fatty acid (TFA) diet on the liver in adult (25 wk) and old (60 wk) senescence-accelerated mice (SAMP8 strain) of both sexes. Our goal was to assess the effects of the diet on protein markers of inflammation and oxidative stress in the liver. METHODS: Male and female mice were placed on life-long diets containing similar amounts of total fat (17%), with differing amounts of TFA: 2% (moderate TFA group) or 0.2% of total energy from TFA (control diet group). At the indicated ages, livers were harvested and evaluated for markers of inflammation and oxidative stress, as well as for enzymes of fat metabolism via immunoblotting. Relative densities of protein bands were determined and compared via a three-factor ANOVA. RESULTS: Compared to males, females demonstrated significantly lower inflammatory protein expression (ICAM-1, MCP-1, COX-2), along with lower expression of the DNA damage marker, Gadd153, and the oxidative stress marker, HO-1. Female mice demonstrated higher expression of antioxidant enzymes (SOD-1, SOD-2, and Ref-1) and lipogenic enzymes (FASN, ACLY) compared to male mice. While HO-1 was elevated in the female mice fed the TFA diet compared to controls, the diet did not affect other markers of oxidative stress or inflammation. However, the diet was associated with significant increases in FASN and ACLY in adult (25 wk) male mice. CONCLUSIONS: Our results suggest sexually dimorphic protein expression in the liver, with female mice demonstrating lower inflammation and increased oxidative stress defenses. Additionally, considering that FASN and ACLY contribute to hepatic lipogenesis, our results suggest a potential mechanism for the dyslipidemia in adult male mice that is associated with TFA diets.

Pediatric vaccine-strain herpes zoster: a case series.

BACKGROUND/OBJECTIVES: Herpes zoster (HZ) is caused by reactivation of the varicella zoster virus (VZV), and typically causes a painful, vesicular, dermatomal rash in adults over the age of fifty. However, HZ has been known to present in immunocompetent pediatric patients, which account for under 1% of total cases. Pediatric cases are typically caused by natural infection with VZV, but among vaccinated children up to half of cases can be due to vaccine-strain VZV. We present two such cases of vaccine-strain HZ in pediatric patients. METHODS: This is a retrospective study of two cases seen at UCLA-affiliated sites. PCR and Sanger sequencing, using previously described PCR primers, determined the presence of two vaccine-strain-specific single nucleotide polymorphisms. RESULTS: We report two cases of vaccine-strain HZ in immunocompetent pediatric patients who had previously received the varicella vaccine, affecting the right thigh in the first patient and the left leg in the second. Varicella-strain VZV positivity was confirmed by PCR. Both patients had received the varicella vaccine at 12 months of age. Both patients achieved complete resolution of symptoms after 7-day courses of acyclovir. CONCLUSIONS: While vaccination against VZV has overall reduced the incidence of both varicella and HZ in US children, given the widespread use of the VZV vaccine, awareness of the possibility of vaccine-induced HZ remains an important consideration.

Abdominal Imaging with Contrast-enhanced Photon-counting CT: First Human Experience.

PURPOSE: To evaluate the performance of a prototype photon-counting detector (PCD) computed tomography (CT) system for abdominal CT in humans and to compare the results with a conventional energy-integrating detector (EID). MATERIALS AND METHODS: The study was HIPAA-compliant and institutional review board-approved with informed consent. Fifteen asymptomatic volunteers (seven men; mean age, 58.2 years ± 9.8 [standard deviation]) were prospectively enrolled between September 2 and November 13, 2015. Radiation dose-matched delayed contrast agent-enhanced spiral and axial abdominal EID and PCD scans were acquired. Spiral images were scored for image quality (Wilcoxon signed-rank test) in five regions of interest by three radiologists blinded to the detector system, and the axial scans were used to assess Hounsfield unit accuracy in seven regions of interest (paired t test). Intraclass correlation coefficient (ICC) was used to assess reproducibility. PCD images were also used to calculate iodine concentration maps. Spatial resolution, noise-power spectrum, and Hounsfield unit accuracy of the systems were estimated by using a CT phantom. RESULTS: In both systems, scores were similar for image quality (median score, 4; P = .19), noise (median score, 3; P = .30), and artifact (median score, 1; P = .17), with good interrater agreement (image quality, noise, and artifact ICC: 0.84, 0.88, and 0.74, respectively). Hounsfield unit values, spatial resolution, and noise-power spectrum were also similar with the exception of mean Hounsfield unit value in the spinal canal, which was lower in the PCD than the EID images because of beam hardening (20 HU vs 36.5 HU; P < .001). Contrast-to-noise ratio of enhanced kidney tissue was improved with PCD iodine mapping compared with EID (5.2 ± 1.3 vs 4.0 ± 1.3; P < .001). CONCLUSION: The performance of PCD showed no statistically significant difference compared with EID when the abdomen was evaluated in a conventional scan mode. PCD provides spectral information, which may be used for material decomposition.

GCN2 is required to increase fibroblast growth factor 21 and maintain hepatic triglyceride homeostasis during asparaginase treatment.

The antileukemic agent asparaginase triggers the amino acid response (AAR) in the liver by activating the eukaryotic initiation factor 2 (eIF2) kinase general control nonderepressible 2 (GCN2). To explore the mechanism by which AAR induction is necessary to mitigate hepatic lipid accumulation and prevent liver dysfunction during continued asparaginase treatment, wild-type and Gcn2 null mice were injected once daily with asparaginase or phosphate buffered saline for up to 14 days. Asparaginase induced mRNA expression of multiple AAR genes and greatly increased circulating concentrations of the metabolic hormone fibroblast growth factor 21 (FGF21) independent of food intake. Loss of Gcn2 precluded mRNA expression and circulating levels of FGF21 and blocked mRNA expression of multiple genes regulating lipid synthesis and metabolism including Fas, Ppara, Pparg, Acadm, and Scd1 in both liver and white adipose tissue. Furthermore, rates of triglyceride export and protein expression of apolipoproteinB-100 were significantly reduced in the livers of Gcn2 null mice treated with asparaginase, providing a mechanistic basis for the increase in hepatic lipid content. Loss of AAR-regulated antioxidant defenses in Gcn2 null livers was signified by reduced Gpx1 gene expression alongside increased lipid peroxidation. Substantial reductions in antithrombin III hepatic expression and activity in the blood of asparaginase-treated Gcn2 null mice indicated liver dysfunction. These results suggest that the ability of the liver to adapt to prolonged asparaginase treatment is influenced by GCN2-directed regulation of FGF21 and oxidative defenses, which, when lost, corresponds with maladaptive effects on lipid metabolism and hemostasis.

Vaginal Self-Sampling for Human Papillomavirus Infection as a Primary Cervical Cancer Screening Tool in a Haitian Population.

BACKGROUND: Human papillomavirus (HPV) testing as primary cervical cancer screening has not been studied in Caribbean women. We tested vaginal self-collection versus physician cervical sampling in a population of Haitian women. METHODS: Participants were screened for high-risk HPV with self-performed vaginal and clinician-collected cervical samples using Hybrid Capture 2 assays (Qiagen, Gaithersburg, MD). Women positive by either method then underwent colposcopy with biopsy of all visible lesions. Sensitivity and positive predictive value were calculated for each sample method compared with biopsy results, with κ statistics performed for agreement. McNemar tests were performed for differences in sensitivity at ≥cervical intraepithelial neoplasia (CIN)-I and ≥CIN-II. RESULTS: Of 1845 women screened, 446 (24.3%) were HPV positive by either method, including 105 (5.7%) only by vaginal swab and 53 (2.9%) only by cervical swab. Vaginal and cervical samples were 91.4% concordant (κ = 0.73 [95% confidence interval, 0.69-0.77], P < 0.001). Overall, 133 HPV-positive women (29.9%) had CIN-I, whereas 32 (7.2%) had ≥CIN-II. The sensitivity of vaginal swabs was similar to cervical swabs for detecting ≥CIN-I (89.1% vs. 87.9%, respectively; P = 0.75) lesions and ≥CIN-II disease (87.5% vs. 96.9%, P = 0.18). Eighteen of 19 cases of CIN-III and invasive cancer were found by both methods. CONCLUSIONS: Human papillomavirus screening via self-collected vaginal swabs or physician-collected cervical swabs are feasible options in this Haitian population. The agreement between cervical and vaginal samples was high, suggesting that vaginal sample-only algorithms for screening could be effective for improving screening rates in this underscreened population.

Outcomes of basal cell carcinomas directly invading the parotid gland.

BACKGROUND: Parotid involvement by basal cell carcinoma (BCC) is rare, and therefore management is controversial. OBJECTIVE: To review the treatment and outcomes of patients with BCC involving the parotid by direct infiltration. METHODS AND MATERIALS: The authors performed a retrospective chart review of BCC cases involving the parotid. RESULTS: From 1994 to 2007, there were 19 cases of BCC involving the parotid gland by direct extension. Nine were primary tumors, and 10 recurrent (nonprimary). Eight tumors were treated with Mohs micrographic surgery (MMS), and 11 with wide local excision (WLE). One patient died of unrelated causes 5 months after treatment, and 2 did not follow up. The remaining 16 cases had an average follow-up of 55.2 months (range, 18-112 months). No primary BCC recurred after treatment. Six of 10 nonprimary BCC (60%) recurred, 2 of 10 metastasized, and 1 of 10 died of metastatic BCC. Two recurrences occurred after MMS, and 4 occurred after WLE with or without parotidectomy. CONCLUSION: Mohs micrographic surgery or WLE with intra-operative margin control seems to be an acceptable first-line treatment for primary BCC involving the parotid. Recurrent BCC involving the parotid gland through direct infiltration has high rates of future recurrence, and adjuvant treatment may be required.

Compared with that of MUFA, a high dietary intake of n-3 PUFA does not reduce the degree of pathology in mdx mice.

Duchenne muscular dystrophy (DMD) is a severe muscle disease that affects afflicted males from a young age, and the mdx mouse is an animal model of this disease. Although new drugs are in development, it is also essential to assess potential dietary therapies that could assist in the management of DMD. In the present study, we compared two diets, high-MUFA diet v. high-PUFA diet, in mdx mice. To generate the high-PUFA diet, a portion of dietary MUFA (oleic acid) was replaced with the dietary essential n-3 PUFA α-linolenic acid (ALA). We sought to determine whether ALA, compared with oleic acid, was beneficial in mdx mice. Consumption of the high-PUFA diet resulted in significantly higher n-3 PUFA content and reduced arachidonic acid content in skeletal muscle phospholipids (PL), while the high-MUFA diet led to higher oleate content in PL. Mdx mice on the high-MUFA diet exhibited 2-fold lower serum creatine kinase activity than those on the high-PUFA diet (P< 0·05) as well as a lower body fat percentage (P< 0·05), but no significant difference in skeletal muscle histopathology results. There was no significant difference between the dietary groups with regard to phosphorylated p65 (an inflammatory marker) in skeletal muscle. In conclusion, alteration of PL fatty acid (FA) composition by the high-PUFA diet made mdx muscle more susceptible to sarcolemmal leakiness, while the high-MUFA diet exhibited a more favourable impact. These results may be important for designing dietary treatments for DMD patients, and future work on dietary FA profiles, such as comparing other FA classes and dose effects, is needed.

Performance evaluation of different albumin assays for the detection of analbuminemia.

Analbuminemia is characterized by the near absence of albumin in the plasma. Different methods are available for measuring albumin levels, but they do not necessarily agree with one another. It is a concern that analbuminemic samples could be falsely characterized due to the incorrect estimation of albumin. The objective of the work was to evaluate the performance of different assays in detecting analbuminemia. Albumin knockout (Alb-/-) mouse plasma was used to test the suitability of different albumin assays for their ability to properly characterize extreme albumin deficiency. Bromocresol green (BCG), bromocresol purple (BCP), enzyme-linked immunosorbent assay (ELISA), liquid chromatography-tandem mass spectrometry (LC-MS/MS), and gel electrophoresis were tested. The LC-MS/MS assay exhibited broad coverage of the amino acid sequence of albumin and indicated 8,400-fold lower (P<0.0001) albumin expression in Alb-/- than wildtype (WT), demonstrating its suitability for identifying extreme albumin deficiency. ELISA estimated albumin at 1.5±0.1 g/dL in WT and was below the detection limit in all Alb-/- samples. Gel electrophoresis yielded consistent results with LC-MS/MS and ELISA. The BCG assay overestimated albumin with apparently appreciable albumin concentrations in Alb-/- mice, yet the assay still indicated a significant difference between genotypes (Alb-/-, 1.2±0.05 g/dL, WT, 3.7±0.1 g/dL, P<0.0001). BCP drastically overestimated albumin and could not successfully identify the known analbuminemic phenotype of Alb-/- mice. By using Alb-/- plasma as a reference material and LC-MS/MS as a reference method, ELISA and gel electrophoresis appear appropriate for identifying analbuminemia, while BCG and BCP are not suitable. It is concluded that dye-binding assays should be avoided when extreme hypoalbuminemia or analbuminemia is suspected.

Albumin is an important factor in the control of serum free fatty acid flux in both male and female mice.

Albumin knockout (Alb-/-) mice exhibit a low plasma free fatty acid (FFA) concentration, but it was not known if the suppressed concentration reflects a lower rate of appearance (Ra) of FFA in the circulation (i.e., lower FFA flux) or if the absence of albumin alters the relationship between FFA flux and concentration. For understanding the role of albumin in FFA transport through the bloodstream, it is not sufficient to rely on FFA concentration data alone. Therefore, we developed a method to study FFA kinetics in Alb-/- mice. Using an albumin-free formulation of [U-13C]palmitate tracer, serum FFA kinetics were tested in Alb-/- and wild-type (WT) mice. Results indicate that the flux of FFA in serum of Alb-/- mice was significantly lower than in WT mice (P < 0.05), while albumin deficiency did not alter the relationship between FFA flux and concentration. Next, to test if suppressed lipolysis might have also been involved in the suppressed FFA kinetics, gene expression of a lipolytic enzyme (adipose triglyceride lipase, Atgl) and a marker of lipolysis (phosphorylation of hormone-sensitive lipase, p-HSL) were measured in adipose tissue. In contrast to the low FFA flux in Alb-/-, both Atgl gene expression and p-HSL protein were significantly higher in adipose tissue of Alb-/- than in WT mice (P < 0.05). Thus, the low FFA flux in Alb-/- appeared to be driven by the absence of albumin's FFA binding functions rather than through regulation of lipolysis, indicating that albumin is an important factor in determining the flux of FFA in circulation.NEW & NOTEWORTHY To improve understanding of the albumin protein's function in vivo, we tested plasma free fatty acid kinetics in albumin knockout mice compared with wild-type mice. Using a new tracer formulation strategy, it was discovered that the appearance rate of free fatty acids in serum is lower in albumin knockout mice than in wild-type mice. The results indicate that albumin is a major controller of free fatty acid kinetics.

A Pilot Validation Study Comparing Fluorescence-Imitating Brightfield Imaging, A Slide-Free Imaging Method, With Standard Formalin-Fixed, Paraffin-Embedded Hematoxylin-Eosin-Stained Tissue Section Histology for Primary Surgical Pathology Diagnosis.

CONTEXT.­: Digital pathology using whole slide images has been recently approved to support primary diagnosis in clinical surgical pathology practices. Here we describe a novel imaging method, fluorescence-imitating brightfield imaging, that can capture the surface of fresh tissue without requiring prior fixation, paraffin embedding, tissue sectioning, or staining. OBJECTIVE.­: To compare the ability of pathologists to evaluate direct-to-digital images with standard pathology preparations. DESIGN.­: One hundred surgical pathology samples were obtained. Samples were first digitally imaged, then processed for standard histologic examination on 4-µm hematoxylin-eosin-stained sections and digitally scanned. The resulting digital images from both digital and standard scan sets were viewed by each of 4 reading pathologists. The data set consisted of 100 reference diagnoses and 800 study pathologist reads. Each study read was compared to the reference diagnosis, and also compared to that reader's diagnosis across both modalities. RESULTS.­: The overall agreement rate, across 800 reads, was 97.9%. This consisted of 400 digital reads at 97.0% versus reference and 400 standard reads versus reference at 98.8%. Minor discordances (defined as alternative diagnoses without clinical treatment or outcome implications) were 6.1% overall, 7.2% for digital, and 5.0% for standard. CONCLUSIONS.­: Pathologists can provide accurate diagnoses from fluorescence-imitating brightfield imaging slide-free images. Concordance and discordance rates are similar to published rates for comparisons of whole slide imaging to standard light microscopy of glass slides for primary diagnosis. It may be possible, therefore, to develop a slide-free, nondestructive approach for primary pathology diagnosis.

Alterations in the Plasma Protein Expression Pattern in Congenital Analbuminemia-A Systematic Review.

Albumin is a highly abundant plasma protein with multiple functions, including the balance of fluid between body compartments and fatty acid trafficking. Humans with congenital analbuminemia (CAA) do not express albumin due to homozygosity for albumin gene mutation. Lessons about physiological control could be learned from CAA. Remarkably, these patients exhibit an apparently normal lifespan, without substantial impairments in physical functionality. There was speculation that tolerance to albumin deficiency would be characterized by significant upregulation of other plasma proteins to compensate for analbuminemia. It is unknown but possible that changes in plasma protein expression observed in CAA are required for the well-documented survival and general wellness. A systematic review of published case reports was performed to assess plasma protein pattern remodeling in CAA patients who were free of other illnesses that would confound interpretation. From a literature search in Pubmed, Scopus, and Purdue Libraries (updated October 2022), concentration of individual plasma proteins and protein classes were assessed. Total plasma protein concentration was below the reference range in the vast majority of CAA patients in the analysis, as upregulation of other proteins was not sufficient to prevent the decline of total plasma protein when albumin was absent. Nonetheless, an impressive level of evidence in the literature indicated upregulated plasma levels of multiple globulin classes and various specific proteins which may have metabolic functions in common with albumin. The potential role of this altered plasma protein expression pattern in CAA is discussed, and the findings may have implications for other populations with hypoalbuminemia.

Albumin Deficiency Reduces Hepatic Steatosis and Improves Glucose Metabolism in a Mouse Model of Diet-Induced Obesity.

Serum albumin facilitates the transport of free fatty acids (FFAs) from adipose tissue to other organs. It was not known if impeding this process could protect from hepatic steatosis and metabolic dysfunction in obesity. We tested whether albumin knockout (Alb-/-) mice would exhibit a reduction in plasma FFA concentration, reduced hepatic lipid accumulation, and improved glucoregulation as compared to wild-type (WT) mice. Male homozygous albumin knockout mice (Alb-/-) and WT controls were fed a low-fat diet (LFD) or high-fat diet (HFD). Alb-/- mice exhibited a similar body weight gain and body composition as WT on both diets. Despite HFD-induced obesity, Alb-/- mice were protected from various comorbidities. Compared to WT mice on the HFD, Alb-/- exhibited lower plasma FFA levels, lower blood glucose levels during glucose tolerance and insulin tolerance tests, and lower hepatic steatosis and inflammation. Alb-/- mice on HFD also exhibited elevated expression of multiple genes in the liver and adipose tissues, such as peroxisome proliferator-activated receptor α in both tissues, as well as glucose transporter-4 and adiponectin in adipose tissues. The results indicate that albumin's FFA transport function may be involved in the development of hepatic lipid accumulation and dysregulated glucose metabolism in obesity.

Coingestion of whey protein and casein in a mixed meal: demonstration of a more sustained anabolic effect of casein.

When consumed separately, whey protein (WP) is more rapidly absorbed into circulation than casein (Cas), which prompted the concept of rapid and slow dietary protein. It is unclear whether these proteins have similar metabolic fates when coingested as in milk. We determined the rate of appearance across the splanchnic bed and the rate of disappearance across the leg of phenylalanine (Phe) from coingested, intrinsically labeled WP and Cas. Either [¹5N]Phe or [¹³C-ring C6]Phe was infused in lactating cows, and the labeled WP and Cas from their milk were collected. To determine the fate of Phe derived from different protein sources, 18 healthy participants were studied after ingestion of one of the following: 1) [¹5N]WP, [¹³C]Cas, and lactose; 2) [¹³C]WP, [¹5N]Cas, and lactose; 3) lactose alone. At 80-120 min, the rates of appearance (R(a)) across the splanchnic bed of Phe from WP and Cas were similar [0.068 ± 0.010 vs. 0.070 ± 0.009%/min; not significant (ns)]. At time 220-260 min, Phe appearance from WP had slowed (0.039 ± 0.008%/min, P < 0.05) whereas Phe appearance from Cas was sustained (0.068 ± 0.013%/min). Similarly, accretion rates across the leg of Phe absorbed from WP and Cas were not different at 80-120 min (0.011 ± 0.002 vs. 0.012 ± 0.003%/min; ns), but they were significantly lower for WP (0.007 ± 0.002%/min) at 220-260 min than for Cas (0.013 ± 0.002%/min) at 220-260 min. Early after meal ingestion, amino acid absorption and retention across the leg were similar for WP and Cas, but as rates for WP waned, absorption and assimilation into skeletal muscle were better retained for Cas.

Albumin knockout mice exhibit reduced plasma free fatty acid concentration and enhanced insulin sensitivity.

Circulating albumin is expected to play a significant role in the trafficking of plasma free fatty acids (FFA) between tissues, such as FFA transfer from adipose tissue to the liver. However, it was not yet known how disrupting FFA binding to albumin in circulation would alter lipid metabolism and any resulting impacts upon control of glycemia. To improve understanding of metabolic control, we aimed to determine whether lack of serum albumin would decrease plasma FFA, hepatic lipid storage, whole body substrate oxidation, and glucose metabolism. Male and female homozygous albumin knockout mice and C57BL/6J wild type controls, each on a standard diet containing a moderate fat content, were studied at 6-8 weeks of age. Indirect calorimetry, glucose tolerance testing, insulin tolerance testing, exercise performance, plasma proteome, and tissue analyses were performed. In both sexes of albumin knockout mice compared to the wild type mice, significant reductions (p < 0.05) were observed for plasma FFA concentration, hepatic triacylglycerol and diacylglycerol content, blood glucose during the glucose tolerance test, and blood glucose during the insulin tolerance test. Albumin deficiency did not reduce whole body fat oxidation over a 24-h period and did not alter exercise performance in an incremental treadmill test. The system-level phenotypic changes in lipid and glucose metabolism were accompanied by reduced hepatic perilipin-2 expression (p < 0.05), as well as increased expression of adiponectin (p < 0.05) and glucose transporter-4 (p < 0.05) in adipose tissue. The results indicate an important role of albumin and plasma FFA concentration in lipid metabolism and glucoregulation.