Obesity and metabolic syndrome are associated with glomerulosclerosis and proteinuria, but the mechanisms are not known. The purpose of this study was to determine if there is altered renal lipid metabolism and increased expression of sterol regulatory elementbinding proteins (SREBPs) in a model of diet-induced obesity. C57BL/6J mice that were fed a high fat, 60 kcal % saturated (lard) fat diet (HFD) developed obesity, hyperglycemia, and hyperinsulinemia compared with those that were fed a low fat, 10 kcal % fat diet (LFD). In contrast, A/J mice were resistant when fed the same diet. C57BL/6J mice with HFD exhibited significantly higher levels of renal SREBP-1 and SREBP-2 expression than those mice with LFD, whereas in A/J mice there were no changes with the same treatment. The increases in SREBP-1 and SREBP-2 expression in C57BL/6J mice resulted in renal accumulation of triglyceride and cholesterol. There were also significant increases in the renal expression of plasminogen activator inhibitor-1 (PAI-1), vascular endothelial growth factor (VEGF), type IV collagen, and fibronectin, resulting in glomerulosclerosis and proteinuria. To determine a role for SREBPs per se in modulating renal lipid metabolism and glomerulosclerosis we performed studies in SREBP-1c ؊/؊ mice. In contrast to control mice, in the SREBP-1c ؊/؊ mice with HFD the accumulation of triglyceride was prevented, as well as the increases in PAI-1, VEGF, type IV collagen, and fibronectin expression. Our results therefore suggest that diet-induced obesity causes increased renal lipid accumulation and glomerulosclerosis in C57BL/6J mice via an SREBP-1c-dependent pathway.Obesity is a known risk factor for cardiovascular disease (1) and type-2 diabetes mellitus (2) and has been proposed to play a role in the pathogenesis of diabetic nephropathy (3). Obesity is one of the defining criteria of the metabolic syndrome as proposed by the National Cholesterol Education Program Adult Treatment Panel III (4) and the World Health Organization (5). The metabolic syndrome, which is characterized by the concurrent existence of obesity, dyslipidemia, hyperglycemia, hyperinsulinemia, and hypertension, has been shown to be a strong and independent risk factor for cardiovascular, and all cause mortality (6, 7) as well as the development of microalbuminuria and chronic kidney disease (8).Obesity is considered a major generator of metabolic syndrome (9). Early in the course of obesity-initiated metabolic syndrome, structural and functional changes similar to diabetic kidney disease occur (10). These changes include glomerular hyperfiltration, glomerular basement membrane thickening, mesangial cell proliferation, mesangial matrix thickening, and expansion of Bowman's capsule (10) and are considered precursors to more severe renal injury. Severe obesity has been associated with the eventual development of focal and segmental glomerulosclerosis (11). Although incompletely understood, several hemodynamic, hormonal, and metabolic factors have been proposed to contribute to t...

Two weeks of dietary intervention (≈4.3% weight loss) reduced hepatic triglycerides by ≈42% in subjects with NAFLD; however, reductions were significantly greater with dietary carbohydrate restriction than with calorie restriction. This may have been due, in part, to enhanced hepatic and whole-body oxidation. This trial was registered at clinicaltrials.gov as NCT01262326.

Diabetic renal disease is associated with lipid deposits in the kidney. The purpose of our study was to determine whether there is altered regulation of the sterol regulatory element-binding proteins (SREBPs) in the diabetic kidney and whether SREBPs mediate the abnormal renal lipid metabolism and diabetic renal disease. In streptozotocin-induced diabetes in the rat, there were marked increases in SREBP-1 and fatty acid synthase (FAS) expression, resulting in increased triglyceride (TG) accumulation. Treatment of diabetic rats with insulin prevented the increased renal expression of SREBP-1 and the accumulation of TG. The role of hyperglycemia in the up-regulation of SREBP-1 was confirmed in renal cells cultured in a high glucose media. High glucose induced increased expression of SREBP-1a and -1c mRNA, SREBP-1 protein, and FAS, resulting in increased TG content. To determine a direct role for SREBP in mediating the increase in renal lipids and glomerulosclerosis, we studied SREBP-1a transgenic mice with increased renal expression of SREBP-1. The increase in SREBP-1 was associated with increased expression of FAS and acetyl CoA carboxylase, resulting in increased TG content, increased expression of transforming growth factor ␤1 and vascular endothelial growth factor, mesangial expansion, glomerulosclerosis, and proteinuria. Our study therefore indicates that renal SREBP-1 expression is increased in diabetes and that SREBP-1 plays an important role in the increased lipid synthesis, TG accumulation, mesangial expansion, glomerulosclerosis, and proteinuria by increasing the expression of transforming growth factor ␤ and vascular endothelial growth factor.

Much of the inflammatory response of the body to bloodborne Gram-negative bacteria occurs in the liver and spleen, the major organs that remove these bacteria and their lipopolysaccharide (LPS, endotoxin) from the bloodstream. We show here that LPS undergoes deacylation in the liver and spleen by acyloxyacyl hydrolase (AOAH), an endogenous lipase that selectively removes the secondary fatty acyl chains that are required for LPS recognition by its mammalian signaling receptor, MD-2-TLR4. We further show that Kupffer cells produce AOAH and are required for hepatic LPS deacylation in vivo. AOAH-deficient mice did not deacylate LPS and, whereas their inflammatory responses to low doses of LPS were similar to those of wild type mice for ϳ3 days after LPS challenge, they subsequently developed pronounced hepatosplenomegaly. Providing recombinant AOAH restored LPS deacylating ability to Aoah ؊/؊ mice and prevented LPS-induced hepatomegaly. AOAH-mediated deacylation is a previously unappreciated mechanism that prevents prolonged inflammatory reactions to Gram-negative bacteria and LPS in the liver and spleen.

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Fluconazole (UK 49,858), a new orally administered bis-triazole, was compared with ketoconazole for activity in synthetic broth dilution susceptibility tests against Candida albicans and also in treatment of experimental systemic candidal infections in rats. In vitro studies indicated that fluconazole activity is less sensitive to acidic medium than is that of ketoconazole. At physiologic pH, fluconazole was approximately 16-fold less active than ketoconazole against 35 representative isolates of C. albicans. Two additional isolates (K-1 and K-3) recovered from patients who had failed ketoconazole therapy were 32-to 64-fold more resistant than the median of each drug for other isolates. In animal studies, fluconazole was very effective in prolonging survival of rats infected with a representative candidal strain. With an inoculum sufficient to kill 29 of 38 sham-treated animals, only 1 of 18 animals treated with 0.5 mg of fluconazole per kg per day died compared with 13 of 20 animals treated with 10.0 mg of ketoconazole per kg per day. However, when similar fluconazole treatment was administered to rats infected with the more resistant strain, K-1, no prolongation of survival was found. Thus, in vivo and in vitro results between strains correlated well for fluconazole. However, in comparing results between drugs, ketoconazole was 16-fold more active in vitro and fluconazole was 20-fold more active in vivo. This discrepancy may be due to drug distribution, modes of drug metabolism, or other pharmacologic differences between the two agents.Systemic candidiasis is a significant complication of immunosuppressive diseases, surgical procedures, and immunosuppressive medical therapies. Standard treatment of systemic candidiasis involves intravenous amphotericin B, which commonly engenders a variety of untoward effects. Other agents have been proposed as also of value in treating or preventing systemic candidiasis (6,15,31). However, their use is more controversial.Fluconazole (UK 49,858) is a new bis-triazole antifungal agent. Because its absorption after oral administration is good (14), fluconazole may be effective as an orally administered therapy. Furthermore, its pharmacologic characteristics differ markedly from those of the related commercially available drug ketoconazole in that fluconazole is renally excreted, readily penetrates cerebrospinal fluid, and has a serum half-life that is sufficiently long to result in high drug levels in plasma with a single daily dose. These differences make fluconazole an interesting possible alternative to currently available therapies.In this report, we present our findings of the activity of fluconazole compared with that of ketoconazole against Candida albicans both in broth dilution susceptibility tests and in experimental systemic infection. Because in vitro test conditions have been found to influence results with other imidazole agents significantly (2,7,8,11,12,19,21,27 MATERIALS AND METHODSAntifungal agents and media. Fluconazole (UK 49,858) and ketoconazole were suppl...

Background and Aims Studies of the prognostic value of Ishak fibrosis stage are lacking. We utilized multi-year follow-up of the Hepatitis C Antiviral Long Term Treatment Against Cirrhosis (HALT-C) Trial to determine whether individual Ishak fibrosis stages predicted clinical outcomes in patients with chronic hepatitis C. Methods Baseline liver biopsies from 1,050 patients with compensated chronic hepatitis C who had failed combination peginterferon and ribavirin were reviewed by a panel of expert hepatopathologists. Fibrosis was staged with the Ishak scale (ranging from 0=no fibrosis to 6=cirrhosis). Biopsy fragmentation and length as well as number of portal tracts were recorded. We compared rates of pre-specified clinical outcomes of hepatic decompensation and hepatocellular carcinoma across individual Ishak fibrosis stages. Results Of 1,050 biopsies 25% were fragmented, 63% >1.5 cm, 69% >10 mm2, and 75% had ≥10 portal tracts. Baseline laboratory markers of liver disease severity were worse and the frequency of esophageal varices higher with increasing Ishak stage (p<.0001). The six-year cumulative incidence of first clinical outcome was 5.6% for stage 2, 16.1% for stage 3, 19.3% for stage 4, 37.8% for stage 5, and 49.3% for stage 6. Among non-fragmented biopsies, the predictive ability of Ishak staging was enhanced; however, no association was observed between Ishak stage and outcomes for fragmented biopsies due to high rates of outcomes for patients with non-cirrhotic stages. Similar results were observed with liver transplantation or liver-related death as the outcome. Conclusions Ishak fibrosis stage predicts clinical outcomes, need for liver transplantation, and liver-related death in patients with chronic hepatitis C. Patients with fragmented biopsies with low Ishak stage may be understaged histologically

Scavengers may benefit from the availability of dead animals along roads that result from collisions with vehicles. However, roads are also considered risky places for many species. Animal habitat selection patterns usually balance energy intake with mortality risk. In this work we analyzed the foraging space use of an assemblage of diurnal scavenging raptors in relation to distance from roads in northwest Patagonia. We selected patches at different distances from roads, and placed a sheep carcass in each patch during the night (n = 18 carcasses in total). In general, carcasses near roads were detected by diurnal scavenging raptors much faster than those far from roads. Smaller raptors such as southern caracaras (Caracara plancus), chimango caracaras (Milvago chimango), and black vultures (Coragyps atratus), were commonly associated with roads both in terms of overall detections and scavenging activities. Southern and chimango caracaras proved to be very good at detecting carcasses, were faster to land in order to feed from them, and were found in greater numbers near roads than far from them. Even though Andean condors (Vultur gryphus) and black-chested buzzard-eagles (Geranoaetus melanoleucus) flew all over the area, they chose to feed far from roads. Our work emphasizes that some scavengers have taken advantage of the novel food resources provided by roads whereas others are reluctant to feed near them. Within a scenario of an increasing number of roads, some species can extend their distributions favoring competition and biotic homogenization processes within original communities. We highlight the importance of taking into account large flying scavengers in land-use planning.Electronic supplementary material The online version of this article (