A Shortcut from Metabolic-Associated Fatty Liver Disease (MAFLD) to Hepatocellular Carcinoma (HCC): c-MYC a Promising Target for Preventative Strategies and Individualized Therapy

Background: Metabolic-associated fatty liver disease (MAFLD) has risen as one of the leading etiologies for hepatocellular carcinoma (HCC). Oncogenes have been suggested to be responsible for the high risk of MAFLD-related HCC. We analyzed the impact of the proto-oncogene c-MYC in the development of human and murine MAFLD and MAFLD-associated HCC. Methods: alb-myctg mice were studied at baseline conditions and after administration of Western diet (WD) in comparison to WT littermates. c-MYC expression was analyzed in biopsies of patients with MAFLD and MAFLD-associated HCC by immunohistochemistry. Results: Mild obesity, spontaneous hyperlipidaemia, glucose intolerance and insulin resistance were characteristic of 36-week-old alb-myctg mice. Middle-aged alb-myctg exhibited liver steatosis and increased triglyceride content. Liver injury and inflammation were associated with elevated ALT, an upregulation of ER-stress response and increased ROS production, collagen deposition and compensatory proliferation. At 52 weeks, 20% of transgenic mice developed HCC. WD feeding exacerbated metabolic abnormalities, steatohepatitis, fibrogenesis and tumor prevalence. Therapeutic use of metformin partly attenuated the spontaneous MAFLD phenotype of alb-myctg mice. Importantly, upregulation and nuclear localization of c-MYC were characteristic of patients with MAFLD and MAFLD-related HCC. Conclusions: A novel function of c-MYC in MAFLD progression was identified opening new avenues for preventative strategies.

Cameroonian Spice Extracts Modulate Molecular Mechanisms Relevant to Cardiometabolic Diseases in SW 872 Human Liposarcoma Cells

The molecular pathophysiology of cardiometabolic diseases is known to be influenced by dysfunctional ectopic adipose tissue. In addition to lifestyle improvements, these conditions may be managed by novel nutraceutical products. This study evaluatedthe effects of 11 Cameroonian medicinal spice extracts on triglyceride accumulation, glucose uptake, reactive oxygen species (ROS) production and interleukin secretion in SW 872 human adipocytes after differentiation with 100 µM oleic acid. Triglyceride content was significantly reduced by all spice extracts. Glucose uptake was significantly increased by Tetrapleura tetraptera, Aframomum melegueta and Zanthoxylum leprieurii. Moreover, Xylopia parviflora, Echinops giganteus and Dichrostachys glomerata significantly reduced the production of ROS. Concerning pro-inflammatory cytokine secretion, we observed that Tetrapleura tetraptera, Echinops giganteus, Dichrostachys glomerata and Aframomum melegueta reduced IL-6 secretion. In addition, Xylopia parviflora, Monodora myristica, Zanthoxylum leprieurii, and Xylopia aethiopica reduced IL-8 secretion, while Dichrostachys glomerata and Aframomum citratum increased it. These findings highlight some interesting properties of these Cameroonian spice extracts in the modulation of cellular parameters relevant to cardiometabolic diseases, which may be further exploited, aiming to develop novel treatment options for these conditions based on nutraceutical products.

Sesame Extract Promotes Chemopreventive Effect of Hesperidin on Early Phase of Diethylnitrosamine-Initiated Hepatocarcinogenesis in Rats

The combination of natural products is an alternative approach to achieving chemopreventive potential. Accordingly, citrus hesperidin exhibits numerous biological activities, including anticarcinogenic activities, while the sesamin in sesame exhibits potent anticancer activities and lipid-lowering effects. We investigated the cancer chemopreventive effects of mixed sesame and orange seed extract (MSO) containing hesperidin and sesamin in diethylnitrosamine (DEN)-induced hepatocarcinogenesis. Rats were injected with DEN once a week for 3 weeks to induce hepatocarcinogenesis. Rats were fed with MSO and various compositions that included sesame extract (SE) and hesperidin. The 10-week administration of MSO more effectively inhibited the number and size of hepatic GST-P-positive foci than hesperidin in DEN-initiated rats. MSO and hesperidin decreased the number of PCNA-positive hepatocytes but increased the apoptotic cells in DEN-induced rats. Furthermore, MSO and its constituents suppressed hepatic triglyceride content concurrently along with the expression of fatty acid synthase. Although the 5-week administration of MSO or hesperidin did not alter hepatic, preneoplastic lesion formation in DEN-initiated rats, it alleviated DEN-induced hepatotoxicity. MSO and its applied compositions did not impact upon the cytochrome P450 system. In conclusion, sesame extract promoted the chemopreventive effect of hesperidin on DEN-induced early stage of hepatocarcinogenesis in rats. The inhibitory mechanisms are likely involved with the induction of cell apoptosis, suppression of cell proliferation and modulation of hepatic lipogenesis. This study may provide revelations in the development of alternative treatments against hepatocellular carcinoma.

Serum Fetuin-B Levels Are Elevated in Women with Metabolic Syndrome and Associated with Increased Oxidative Stress

Previous studies on serum fetuin-B (fetuin-like protein IRL685) have investigated its association with T2DM; however, the reason for the variation in serum fetuin-B and its regulatory factors in metabolic disease remain unclear. Here, we evaluated serum fetuin-B levels in women with newly diagnosed MetS and performed multiple interventions to investigate the role of fetuin-B in the pathogenesis of MetS. Serum fetuin-B levels were assessed using ELISA. Bioinformatics analysis was performed to analyze fetuin-B-related genes and signaling pathways. Additionally, oxidative stress parameters were measured in the in vitro study. For subgroup analyses, we performed EHC, OGTT, and treatment with a GLP-1RA to investigate the regulatory factors of serum fetuin-B. We found that in comparison with healthy subjects, serum fetuin-B levels were markedly increased in women with MetS. Further, serum fetuin-B showed a positive correlation with WHR, FAT%, TG, FBG, HbA1c, FIns, HOMA-IR, VAI, and LAP. Bioinformatics analysis revealed that most fetuin-B-related core genes were involved in cholesterol metabolism and fat decomposition. Consistent with this finding, multivariate regression analysis showed that triglyceride content and WHR were independently associated with serum fetuin-B. We also observed that serum fetuin-B levels were markedly elevated in healthy subjects after glucose loading and in women with MetS during EHC. In vitro, overexpression of fetuin-B promoted oxidative stress in HepG2 cell. After 6 months of treatment with a GLP-1RA, serum fetuin-B levels in women with MetS decreased following an improvement in metabolism and insulin sensitivity. Therefore, serum fetuin-B is associated with MetS, which may serve as a biomarker of oxidative stress. This trial is registered with ChiCTR-OCC-11001422.

Novel Facets of the Liver Transcriptome Are Associated with the Susceptibility and Resistance to Lipid-Related Metabolic Disorders in Periparturient Holstein Cows

Lipid-related metabolic disorders (LRMD) are prevalent in early lactation dairy cows, and have detrimental effects on productivity and health. Our objectives were to identify cows resistant or susceptible to LRMD using a ketosis induction protocol (KIP) to discover differentially expressed liver genes and metabolic pathways associated with disposition. Clustering cows based on postpartum lipid metabolite concentrations within dietary treatments identified cows more or less susceptible (MS vs. LS) to LRMD within the control treatment, and more or less resistant (MR vs. LR) within the KIP treatment. Whole-transcriptome RNA sequencing was performed on liver samples (−28, +1, and +14 days relative to calving) to assess differential gene and pathway expression (LS vs. MS; MR vs. LR; n = 3 cows per cluster). Cows within the MS and LR clusters had evidence of greater blood serum β-hydroxybutyrate concentration and liver triglyceride content than the LS and MR clusters, respectively. The inferred metabolism of differentially expressed genes suggested a role of immune response (i.e., interferon-inducible proteins and major histocompatibility complex molecules). Additionally, unique roles for glutathione metabolism and eicosanoid metabolism in modulating susceptibility and resistance, respectively, were implicated. Overall, this research provides novel insight into the role of immunometabolism in LRMD pathology, and suggests the potential for unique control points for LRMD progression and severity.

Amber Extract Reduces Lipid Content in Mature 3T3-L1 Adipocytes by Activating the Lipolysis Pathway

Amber—the fossilized resin of trees—is rich in terpenoids and rosin acids. The physiological effects, such as antipyretic, sedative, and anti-inflammatory, were used in traditional medicine. This study aims to clarify the physiological effects of amber extract on lipid metabolism in mouse 3T3-L1 cells. Mature adipocytes are used to evaluate the effect of amber extract on lipolysis by measuring the triglyceride content, glucose uptake, glycerol release, and lipolysis-related gene expression. Our results show that the amount of triacylglycerol, which is stored in lipid droplets in mature adipocytes, decreases following 96 h of treatment with different concentrations of amber extract. Amber extract treatment also decreases glucose uptake and increases the release of glycerol from the cells. Moreover, amber extract increases the expression of lipolysis-related genes encoding perilipin and hormone-sensitive lipase (HSL) and promotes the activity of HSL (by increasing HSL phosphorylation). Amber extract treatment also regulates the expression of other adipocytokines in mature adipocytes, such as adiponectin and leptin. Overall, our results indicate that amber extract increases the expression of lipolysis-related genes to induce lipolysis in 3T3-L1 cells, highlighting its potential for treating various obesity-related diseases.

Response to Comment on “Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women”

In evaluating any randomized clinical trial, it is important to determine whether baseline differences between groups could have affected the primary outcome. In our study, muscle insulin sensitivity, which was identical in both groups at baseline, improved after nicotinamide mononucleotide (NMN), not placebo, therapy. Differences in baseline intrahepatic triglyceride content between groups do not negate the effects of NMN observed in muscle.

Differences between Active and Semi-Active Students Regarding the Parameters of Body Composition Using Bioimpedance and Magnetic Bioresonance Technologies

The aim of the study was to identify differences in obesity-related parameters between active sports students and semi-active or sedentary students, differentiated by sex, in order to optimize health. The study sample included 286 students, of which the male experimental sample consisted of 86 active sports students, age X ± SD 21.25 ± 0.32 years; height X ± SD 181.08 ± 3.52 cm; control group consisting of 89 semi-active students aged X ± SD 21.07 ± 0.1.13 years; height X ± SD 182.11 ± 1.32. The female experimental sample includes 57 active sports students, age X ± SD 21.02 ± 0.92 years; height X ± SD 167.48 ± 1.34 cm; the control group includes 54 semi-active students aged X ± SD 21.57 ± 0.1.98 years; height X ± SD 168.42 ± 1.76. The study used a thalliometer, Tanita Health Ware software and Quantum Resonance Magnetic Analyzer equipment to investigate height (cm), Body Mass Index (BMI), muscle mass (kg, %), as well as the obesity analysis report, and componential analysis of body and nourishment. The differences registered between the samples of active and semi-active sports subjects were predominantly statistically significant for p < 0.05. The differences registered between the samples of active and semi-active sports subjects were predominantly statistically significant for p < 0.05. The most important parameters regarding obesity and body composition that registered significant differences between the two male groups were in favor of the group of active athletes: triglyceride content of abnormal coefficient 0.844 (CI95% 0.590–1.099), abnormal lipid metabolism coefficient 0.798 (CI95% 1.091–0.504), obesity degree of body (ODB %) 10.290 (CI95% 6.610–13.970), BMI 2.326 (CI95% 1.527–3.126), body fat (kg) 2.042 (CI95% 0.918–3.166), muscle volume (kg) 2.565 (CI95% 1.100–4.031), Lean body weight (kg) 2.841 (CI95% 5.265–0.418). In the case of female samples, the group of active sportswomen registered the biggest differences compared to the group of students who were significantly active in the parameters: abnormal lipid metabolism coefficient 1.063 (CI95% 1.380–0.746), triglyceride content of abnormal coefficient 0.807 (CI95% 0.437–1.178), obesity degree of body (ODB%) 8.082 (CI95% 2.983–13.181), BMI 2.285 (CI95% 1.247–3.324), body fat (kg) 2.586 (CI95% 0.905–4.267), muscle volume (kg) 2.570 (CI95% 0.154–4.985), lean body weight (kg) 4.118 (CI95% 1.160–7.077). The results of the study directly facilitate the understanding of the complexity of the impact of obesity on multiple parameters of body composition and health.

Functional peroxisomes are required for heat shock-induced hormesis in Caenorhabditis elegans

Exact mechanisms of heat shock induced lifespan extension, while documented across species, are still not well understood. Here we put forth evidence that fully functional peroxisomes are required for the activation of the canonical heat shock response and heat-induced hormesis in C. elegans. While during heat shock the HSP-70 chaperone is strongly upregulated in the wild-type (WT) as well as in the absence of peroxisomal catalase (Δctl-2 mutant), the small heat shock proteins display modestly increased expression in the mutant. Nuclear localization of HSF-1 is reduced in the Δctl-2 mutant. In addition, heat-induced lifespan extension, observed in the WT, is absent in the Δctl-2 mutant. Activation of the antioxidant response, the pentose phosphate pathway and increased triglyceride content are the most prominent changes observed during heat shock in the WT worm, but not in the Δctl-2 mutant. Involvement of peroxisomes in the cell-wide response to transient heat shock reported here gives new insight into the role of organelle communication in the organisms stress response.

Dietary Restriction Induces a Stable Metabolic Obesity Phenotype in Drosophila Melanogaster

ObjectiveChallenges associated with current nutritional models to induce obesity in Drosophila melanogaster created a rationale for this study. The objective of the study was to investigate biochemical changes associated with high-fat diet (HFD), high sucrose diet (HSD), and a protein-restricted diet (DR) to induce a healthy metabolic obesity state. Drosophila melanogaster were fed to four experimental diets: regular food (control), HFD, HSD, and DR, for four weeks. Peristaltic waves were measured on 3rd instar larvae, while negative geotaxis, body mass, catalase activity; and total triglycerides, sterol, and protein were measured in adult Drosophila melanogaster.ResultsDR produced a Drosophila melanogaster phenotype which had superior adaptive advantages than that generated from HFD and HSD. HFD was the best phenotype during larval stages; however, locomotory, body mass, triglyceride, sterol concentrations, and catalase activity were highest in the DR phenotype during adulthood. High catalase activity and high triglyceride content demonstrated a balanced and healthy metabolic obesity status than in other phenotypes in the adult stage. Evolutionary changes are responsible for the selective advantage of the DR phenotype over the HFD phenotype. Prospective studies to guide therapy and community behavior should place more emphasis on the DR phenotypes in Drosophila melanogaster.