Proteomic identification and characterization of hepatic glyoxalase 1 dysregulation in non-alcoholic fatty liver disease

Background: Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. However, its molecular pathogenesis is incompletely characterized and clinical biomarkers remain scarce. The aims of these experiments were to identify and characterize liver protein alterations in an animal model of early, diet-related, liver injury and to assess novel candidate biomarkers in NAFLD patients. Methods: Liver membrane and cytosolic protein fractions from high fat fed apolipoprotein E knockout (ApoE−/−) animals were analyzed by quantitative proteomics, utilizing isobaric tags for relative and absolute quantitation (iTRAQ) combined with nano-liquid chromatography and tandem mass spectrometry (nLC-MS/MS). Differential protein expression was confirmed independently by immunoblotting and immunohistochemistry in both murine tissue and biopsies from paediatric NAFLD patients. Candidate biomarkers were analyzed by enzyme-linked immunosorbent assay in serum from adult NAFLD patients. Results: Through proteomic profiling, we identified decreased expression of hepatic glyoxalase 1 (GLO1) in a murine model. GLO1 protein expression was also found altered in tissue biopsies from paediatric NAFLD patients. In vitro experiments demonstrated that, in response to lipid loading in hepatocytes, GLO1 is first hyperacetylated then ubiquitinated and degraded, leading to an increase in reactive methylglyoxal. In a cohort of 59 biopsy-confirmed adult NAFLD patients, increased serum levels of the primary methylglyoxal-derived advanced glycation endproduct, hydroimidazolone (MG-H1) were significantly correlated with body mass index (r = 0.520, p < 0.0001). Conclusion: Collectively these results demonstrate the dysregulation of GLO1 in NAFLD and implicate the acetylation-ubquitination degradation pathway as the functional mechanism. Further investigation of the role of GLO1 in the molecular pathogenesis of NAFLD is warranted. Keywords: Non-alcoholic fatty liver disease, Glyoxalase, Methylglyoxal, Proteomics, iTRA

Potential therapeutic effects of branched-chain amino acids supplementation on resistance exercise-based muscle damage in humans

Branched-chain amino acids (BCAA) supplementation has been considered an interesting nutritional strategy to improve skeletal muscle protein turnover in several conditions. In this context, there is evidence that resistance exercise (RE)-derived biochemical markers of muscle soreness (creatine kinase (CK), aldolase, myoglobin), soreness, and functional strength may be modulated by BCAA supplementation in order to favor of muscle adaptation. However, few studies have investigated such effects in well-controlled conditions in humans. Therefore, the aim of this short report is to describe the potential therapeutic effects of BCAA supplementation on RE-based muscle damage in humans. The main point is that BCAA supplementation may decrease some biochemical markers related with muscle soreness but this does not necessarily reflect on muscle functionality

Circadian Clocks as Modulators of Metabolic Comorbidity in Psychiatric Disorders

Psychiatric disorders such as schizophrenia, bipolar disorder, and major depressive disorder are often accompanied by metabolic dysfunction symptoms, including obesity and diabetes. Since the circadian system controls important brain systems that regulate affective, cognitive, and metabolic functions, and neuropsychiatric and metabolic diseases are often correlated with disturbances of circadian rhythms, we hypothesize that dysregulation of circadian clocks plays a central role in metabolic comorbidity in psychiatric disorders. In this review paper, we highlight the role of circadian clocks in glucocorticoid, dopamine, and orexin/melanin-concentrating hormone systems and describe how a dysfunction of these clocks may contribute to the simultaneous development of psychiatric and metabolic symptoms

Circadian rhythms versus daily patterns in human physiology and behavior

The endogenous circadian timekeeping system modulates human physiology and behavior with a near 24 h periodicity conferring adaptation to the ~24 h solar light-dark cycle. Thus, the circadian timekeeping system times physiology and behavior so that it is prepared for environmental changes. The term circadian implies an endogenous “clock-driven” process. However, not all observed daily patterns in physiology and behavior are clock driven and instead may be due to environmental or behavioral factors. For example, the barren rock on the top of a mountain shows a daily temperature oscillation that is not endogenous to the rock but instead is caused by the sun heating the rock during the day and radiative heat loss after sunset. Other factors such as wind, rain, and cloud cover impact the observed daily temperature oscillation of the rock. Similarly, some of the daily patterns observed in physiology and behavior are driven by external factors, while others arise from the interaction between circadian and behavioral processes (e.g., sleep-wake, fasting-feeding). To improve understanding of the mechanisms underlying observed daily patterns in physiology and behavior in humans, a variety of circadian protocols have been implemented (Tables 13.1 and 13.2). These protocols will be reviewed in the following pages, and the strengths and limitations of each will be discussed. First, we review markers of the endogenous clock in humans

CLEC4F Is an Inducible C-Type Lectin in F4/80-Positive Cells and Is Involved in Alpha-Galactosylceramide Presentation in Liver

Contains fulltext : 118089.pdf (publisher's version ) (Open Access)CLEC4F, a member of C-type lectin, was first purified from rat liver extract with high binding affinity to fucose, galactose (Gal), N-acetylgalactosamine (GalNAc), and un-sialylated glucosphingolipids with GalNAc or Gal terminus. However, the biological functions of CLEC4F have not been elucidated. To address this question, we examined the expression and distribution of murine CLEC4F, determined its binding specificity by glycan array, and investigated its function using CLEC4F knockout (Clec4f-/-) mice. We found that CLEC4F is a heavily glycosylated membrane protein co-expressed with F4/80 on Kupffer cells. In contrast to F4/80, CLEC4F is detectable in fetal livers at embryonic day 11.5 (E11.5) but not in yolk sac, suggesting the expression of CLEC4F is induced as cells migrate from yolk cells to the liver. Even though CLEC4F is not detectable in tissues outside liver, both residential Kupffer cells and infiltrating mononuclear cells surrounding liver abscesses are CLEC4F-positive upon Listeria monocytogenes (L. monocytogenes) infection. While CLEC4F has strong binding to Gal and GalNAc, terminal fucosylation inhibits CLEC4F recognition to several glycans such as Fucosyl GM1, Globo H, Bb3 approximately 4 and other fucosyl-glycans. Moreover, CLEC4F interacts with alpha-galactosylceramide (alpha-GalCer) in a calcium-dependent manner and participates in the presentation of alpha-GalCer to natural killer T (NKT) cells. This suggests that CLEC4F is a C-type lectin with diverse binding specificity expressed on residential Kupffer cells and infiltrating monocytes in the liver, and may play an important role to modulate glycolipids presentation on Kupffer cells

Circadian rhythms versus daily patterns in human physiology and behavior

The endogenous circadian timekeeping system modulates human physiology and behavior with a near 24 h periodicity conferring adaptation to the ~24 h solar light-dark cycle. Thus, the circadian timekeeping system times physiology and behavior so that it is prepared for environmental changes. The term circadian implies an endogenous “clock-driven” process. However, not all observed daily patterns in physiology and behavior are clock driven and instead may be due to environmental or behavioral factors. For example, the barren rock on the top of a mountain shows a daily temperature oscillation that is not endogenous to the rock but instead is caused by the sun heating the rock during the day and radiative heat loss after sunset. Other factors such as wind, rain, and cloud cover impact the observed daily temperature oscillation of the rock. Similarly, some of the daily patterns observed in physiology and behavior are driven by external factors, while others arise from the interaction between circadian and behavioral processes (e.g., sleep-wake, fasting-feeding). To improve understanding of the mechanisms underlying observed daily patterns in physiology and behavior in humans, a variety of circadian protocols have been implemented (Tables 13.1 and 13.2). These protocols will be reviewed in the following pages, and the strengths and limitations of each will be discussed. First, we review markers of the endogenous clock in humans