- Non-alcoholic Fatty Liver Disease and Gastric Bypass Surgery Regulate Serum And Hepatic Levels of Pyruvate Kinase Isoenzyme M2. [Journal Article]
- AJAm J Physiol Endocrinol Metab 2018 Feb 20
- Treatment of non-alcoholic fatty liver disease (NAFLD) focuses on the underlying metabolic syndrome, and Roux-en-Y gastric bypass surgery (RYGB) remains one of the most effective options. In rodents ...
Treatment of non-alcoholic fatty liver disease (NAFLD) focuses on the underlying metabolic syndrome, and Roux-en-Y gastric bypass surgery (RYGB) remains one of the most effective options. In rodents and human patients, RYGB induces an increase in the gene and protein expression levels of the M2 isoenzyme of Pyruvate Kinase (PKM2) in the jejunum. Since PKM2 can be secreted in the circulation, our hypothesis was that the circulating levels of PKM2 increase after RYGB. Our data, however, revealed an unexpected finding and a potential new role of PKM2 for the natural history of metabolic syndrome and NAFLD. Contrary to our initial hypothesis, RYGB-treated patients had decreased PKM2 blood levels compared to a well-matched group of patients with severe obesity prior to RYGB. Interestingly, PKM2 serum concentration correlated with BMI before but not after the surgery. This prompted us to evaluate other potential mechanisms and sites of PKM2 regulation by the metabolic syndrome and RYGB. We found that in patients with NAFLD and NASH, the liver had increased PKM2 expression levels, and the enzyme appears to be specifically localized in Kupffer cells. The study of murine models of metabolic syndrome and NASH replicated this pattern of expression, further suggesting a metabolic link between hepatic PKM2 and NAFLD. Therefore, we conclude that PKM2 serum and hepatic levels increase in both metabolic syndrome and NAFLD and decrease after RYGB. Thus, PKM2 may represent a new target for monitoring and treatment of NAFLD.
- PycnogenolRprotects against diet-induced hepatic steatosis in Apolipoprotein-E deficient mice. [Journal Article]
- AJAm J Physiol Endocrinol Metab 2018 Feb 20
- Pycnogenol (PYC), a combination of active flavonoids derived from French maritime pine bark, is a natural antioxidant that has various pharmacological activities. Here, we investigated the beneficial...
Pycnogenol (PYC), a combination of active flavonoids derived from French maritime pine bark, is a natural antioxidant that has various pharmacological activities. Here, we investigated the beneficial effect of PYC on diet-induced hepatic steatosis. Apolipoprotein E (ApoE)-deficient male mice were administered PYC at oral doses of 30 or 100 mg•kg-1 •day-1 for two weeks in advance and were then fed a high cholesterol and fat diet (HCD) for eight weeks. Biochemical, immunohistochemical, and gene expression analyses were conducted to explore the effect of PYC on lipid metabolism in ApoE-deficient mice on a HCD. Short-term treatment with HCD in ApoE-deficient mice induced hepatic injuries, such as lipid metabolism disorder and hepatic histopathological changes. We found that PYC reduced body weight and the increase of serum lipids that had been caused by HCD. Supplementation of PYC significantly reduced lipid deposition in the liver, as shown by the lowered hepatic lipid content and histopathological lesions. We subsequently detected genes related to lipid metabolism and inflammatory cytokines. The study showed that PYC markedly suppressed the expression of genes related to hepatic lipogenesis, fatty acid uptake, and lipid storage while increasing the lipolytic gene, which thus reduced hepatic lipid content. Furthermore, PYC mainly reduced the expression of inflammatory cytokines and the infiltration of inflammatory cells, which were resistant to the development of hepatic steatosis. These results demonstrate that PYC protects against the occurrence and development of hepatic steatosis and may provide a new prophylactic approach for non-alcoholic fatty liver disease (NAFLD).
- FEATURES OF EXCRETION OF MELATONIN IN URINE IN PATIENTS WITH TYPE 2 DIABETES MELLITUS AND NON-ALCOHOLIC FATTY LIVER DISEASE WITH MANIFESTATIONS OF FIBROSIS AND ITS RELATIONSHIP WITH CERTAIN METABOLIC AND IMMUNOLOGICAL INDICATORS. [Journal Article]
- GMGeorgian Med News 2018; (274):103-107
- To study the features of secretion of melatonin in the urine in patients with DM type 2 and NAFLD with manifestations of fibrosis and its relationship with some metabolic and immunological parameters...
To study the features of secretion of melatonin in the urine in patients with DM type 2 and NAFLD with manifestations of fibrosis and its relationship with some metabolic and immunological parameters, 23 patients with DM type 2 and NAFLD were examined. The degree of fibrosis in patients was diagnosed on the basis of static elastography and the study of indirect fibrosis markers 16 persons (72%) diagnosed with mild fibrosis (F0-F1 on METAVIR), 5 people (18.2%) - with moderate fibrosis (F2-F3 on METAVIR). Only 2 (8.7%) patients did not have any fibrotic disorders, so they were excluded from the further study. All patients underwent determination of melatonin excretion of albumin and in daily urine, as well as the determination of homocysteine in the blood. The level of excretion of melatonin in the urine in patients with DM type 2 and NAFLD did not depend on the degree of fibrosis and on the average was 89.50±16.66 mmol/day, which exceeded the reference values. It has been established that the increase in melatonin level in patients with DM type 2 and NAFLD is associated with the presence of fibrotic changes in the liver and a decrease in the activity of the inflammatory process. In addition, a direct correlation was found between the excretion of melatonin and homocysteine (r=0.43), as well as between melatonin and albumin excretion in the urine (r=0.20). Thus, an increased level of excretion of melatonin in the urine can be not only a marker of liver fibrosis, but also a predictor of cardiovascular disorders in patients with DM type 2 and NAFLD.
- Nonylphenol aggravates non-alcoholic fatty liver disease in high sucrose-high fat diet-treated rats. [Journal Article]
- SRSci Rep 2018 Feb 19; 8(1):3232
- Exposure to environmental endocrine disruptors (EEDs) contributes to the pathogenesis of many metabolic disorders. Here, we have analyzed the effect of the EED-nonylphenol (NP) on the promotion of no...
Exposure to environmental endocrine disruptors (EEDs) contributes to the pathogenesis of many metabolic disorders. Here, we have analyzed the effect of the EED-nonylphenol (NP) on the promotion of non-alcoholic fatty liver disease (NAFLD) in rats fed high sucrose-high fat diet (HSHFD). Fifty Sprague-Dawley rats were divided into five groups: controls fed a normal diet (C-ND); HSHFD-fed controls (C-HSHFD); and rats fed a HSHFD combined with NP at doses of 0.02 μg/kg/day (NP-L-HSHFD), 0.2 μg/kg/day (NP-M-HSHFD), and 2 μg/kg/day (NP-H-HSHFD). Subchronic exposure to NP coupled with HSHFD increased daily water and food intake (p < 0.05), hepatic echogenicity and oblique liver diameter (p < 0.05), and plasma levels of alanine aminotransferase, aspartate aminotransferase, total cholesterol, triglycerides, and low density lipoprotein cholesterol (p < 0.05). Combined exposure to NP and HSHFD induced macrovesicular steatosis with dilation and congestion of the central vein, liver inflammatory cell infiltration, and expression of genes regulating lipid metabolism, SREBP-1C, FAS, and Ucp2. These results demonstrate that NP aggravates NAFLD in HSHFD-treated rats by up-regulating lipogenic genes, and that HSHFD increases the toxic effects of NP. Thus subchronic NP exposure may lead to NAFLD, especially when combined with a high-sucrose/high-fat diet.
- Bax Inhibitor-1 protects from Non-Alcoholic Steatohepatitis by limiting IRE1α signaling. [Journal Article]
- HepHepatology 2018 Feb 19
- CONCLUSIONS: Targeting IRE1α-dependent NLRP3 inflammasome signaling with pharmacological agents or via BI-1 may represent a tangible therapeutic strategy for NASH. This article is protected by copyright. All rights reserved.
- Correlation of blood glucose, serum chemerin and insulin resistance with NAFLD in patients with type 2 diabetes mellitus. [Journal Article]
- ETExp Ther Med 2018; 15(3):2936-2940
- Non-alcoholic fatty liver disease (NAFLD) is a form of clinical syndrome characterized by the fatty degeneration in liver histology and should be further investigated. The aim of the study was to inv...
Non-alcoholic fatty liver disease (NAFLD) is a form of clinical syndrome characterized by the fatty degeneration in liver histology and should be further investigated. The aim of the study was to investigate the effects of blood glucose, serum chemerin and insulin resistance on non-alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus to provide a basis for the prevention and treatment thereof. In total, 300 patients with type 2 diabetes mellitus treated and admitted into the Endocrinology Department of our hospital from June 2015 to June 2017 were enrolled and divided into the simple type 2 diabetes mellitus (group A) and concurrent NAFLD (group B) groups. The sex, age, body mass index (BMI), blood pressure, blood biochemical indexes and chemerin level were compared between the two groups. The patients in group B were further divided into the mild fatty liver (group B1), moderate fatty liver (group B2) and severe fatty liver (group B3) groups. The sex, age, BMI blood pressure, blood biochemical indexes and chemerin level were also compared among the three groups. Finally, the risk factors of type 2 diabetes mellitus complicated by NAFLD were analyzed via logistic regression. The BMI, fasting plasma glucose (FPG), 2 h post-prandial plasma glucose (2hPG), triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), alanine aminotransferase (ALT), fasting insulin (FINS), homeostasis model assessment of insulin resistance (HOMA-IR) and HOMA-β indexes and serum chemerin level in group B were significantly higher than those in group A (P<0.05 or P<0.01). Notably, the aggravation of NAFLD, the aforementioned indexes were obviously increased (P<0.05 or P<0.01). The regression analysis revealed that BMI, FPG, TC, LDL-c, FINS, HOMA-IR and chemerin were risk factors of concurrent NAFLD. Thus, type 2 diabetes mellitus complicated by NAFLD is closely associated with severe glucose-lipid metabolism disorder and insulin resistance, and BMI, FPG, TC, LDL-c, FINS, HOMA-IR and chemerin constitute risk factors of concurrent NAFLD.
- Correlation between PPAR-α methylation level in peripheral blood and atherosclerosis of NAFLD patients with DM. [Journal Article]
- ETExp Ther Med 2018; 15(3):2727-2730
- We investigated the correlation between the methylation levels of peroxisome proliferator-activated receptor-α (PPAR-α) in the peripheral blood and atherosclerosis in patients with nonalcoholic fatty...
We investigated the correlation between the methylation levels of peroxisome proliferator-activated receptor-α (PPAR-α) in the peripheral blood and atherosclerosis in patients with nonalcoholic fatty liver disease (NAFLD) with diabetes mellitus (DM). A total of 50 normal subjects (group N) and 50 NAFLD patients with DM (group M) were selected at Qilu Hospital of Shandong University. The levels of total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL) and low-density lipoprotein (LDL) in groups N and M were detected. The mRNA and protein expressions of PPAR-α in groups N and M were detected using reverse transcription polymerase chain reaction (PCR) and immunofluorescence. The differences in expression of PPAR-α in group N and M and the correlation between PPAR-α methylation level and atherosclerosis were analyzed using SPSS17.0 statistical software. TC, TG, HDL and LDL in groups N and M were significantly different (P<0.01). Hematoxylin and eosin staining showed that the histopathological damage was severe in group M. PCR and immunofluorescence showed that PPAR-α was significantly higher in N than in group M (P<0.01). The abnormal expression of PPAR-α is closely related to atherosclerosis, indicating that the correlation between PPAR-α methylation levels in peripheral blood and atherosclerosis of NAFLD patients with DM can provide a new direction of diagnosis and treatment.
- Proteomic identification and characterization of hepatic glyoxalase 1 dysregulation in non-alcoholic fatty liver disease. [Journal Article]
- PSProteome Sci 2018; 16:4
- CONCLUSIONS: 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.
- An Integrated Understanding of the Rapid Metabolic Benefits of a Carbohydrate-Restricted Diet on Hepatic Steatosis in Humans. [Journal Article]
- CMCell Metab 2018 Feb 07
- A carbohydrate-restricted diet is a widely recommended intervention for non-alcoholic fatty liver disease (NAFLD), but a systematic perspective on the multiple benefits of this diet is lacking. Here,...
A carbohydrate-restricted diet is a widely recommended intervention for non-alcoholic fatty liver disease (NAFLD), but a systematic perspective on the multiple benefits of this diet is lacking. Here, we performed a short-term intervention with an isocaloric low-carbohydrate diet with increased protein content in obese subjects with NAFLD and characterized the resulting alterations in metabolism and the gut microbiota using a multi-omics approach. We observed rapid and dramatic reductions of liver fat and other cardiometabolic risk factors paralleled by (1) marked decreases in hepatic de novo lipogenesis; (2) large increases in serum β-hydroxybutyrate concentrations, reflecting increased mitochondrial β-oxidation; and (3) rapid increases in folate-producing Streptococcus and serum folate concentrations. Liver transcriptomic analysis on biopsy samples from a second cohort revealed downregulation of the fatty acid synthesis pathway and upregulation of folate-mediated one-carbon metabolism and fatty acid oxidation pathways. Our results highlight the potential of exploring diet-microbiota interactions for treating NAFLD.
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- JIP3 knockout protects mice against high fat diet-induced liver injury. [Journal Article]
- BBBiochem Biophys Res Commun 2018 Feb 15
- Multiple pathways contribute to nonalcoholic fatty liver disease (NAFLD) in response to high fat diets (HFD). A homolog of mammalian JNK-interacting protein 3 (JIP3), also known as JSAP-1, activates ...
Multiple pathways contribute to nonalcoholic fatty liver disease (NAFLD) in response to high fat diets (HFD). A homolog of mammalian JNK-interacting protein 3 (JIP3), also known as JSAP-1, activates different components in various signaling pathways to modulate cellular processes. The purpose of this study was to examine the role of JIP3 in obesity-related pathologies pathway. Wild-type (WT) C57BL/6 and JIP3-knockout (JIP3-/-) mice were randomized to chow or HFD. HFD-fed WT mice increased hepatic JIP3 expression. Mice lacking JIP3 exhibited reduced weight gain, hepatic steatosis, insulin resistance, lipid accumulation, oxidative stress and inflammatory response in mice fed a HFD, which were, importantly, dependent on various signaling pathways. Lipogenesis-linked pathway was inhibited in JIP3-/-mice after HFD, while PPARα/γ were increased. Additionally, JIP3-/-inhibited hepatic oxidative stress, evidenced by down-regulation of total reactive oxygen species (ROS), H2O2, O2.-, malondialdehyde (MDA), xanthine oxidase (XO), inducible nitric oxide synthase (iNOS), and up-regulation of superoxide dismutase (SOD) and total antioxidant capacity (TAC) in mice after HFD feeding, which might be related to nuclear respiratory factor 2 (Nrf-2) pathway activation. Further, inflammatory response was blocked in JIP3-/-mice fed with HFD. The process might be attributed to the suppression of toll-like receptors (TLRs), p-nuclear factor kappa B (NF-κB) and p-c-Jun-N-terminal kinase (JNK). Thus, JIP3 absence is associated with decreased lipogenesis, oxidative stress and inflammation, supplying a new target for NAFLD treatment.