Although physical activity (PA) is crucial in the prevention and clinical management of nonalcoholic fatty liver disease, most individuals with this chronic disease are inactive and do not achieve ...recommended amounts of PA. There is a robust and consistent body of evidence highlighting the benefit of participating in regular PA, including a reduction in liver fat and improvement in body composition, cardiorespiratory fitness, vascular biology, and health-related quality of life. Importantly, the benefits of regular PA can be seen without clinically significant weight loss. At least 150 min of moderate or 75 min of vigorous intensity PA are recommended weekly for all patients with nonalcoholic fatty liver disease, including those with compensated cirrhosis. If a formal exercise training program is prescribed, aerobic exercise with the addition of resistance training is preferred. In this roundtable document, the benefits of PA are discussed, along with recommendations for 1) PA assessment and screening; 2) how best to advise, counsel, and prescribe regular PA; and 3) when to refer to an exercise specialist.
OBJECTIVE—The purpose of this research was to determine how dietary bile acids repress hepatic expression of paraoxonase 1 (PON1).
METHODS AND RESULTS—C57BL/6 mice and C3H/HeJ mice, having different ...susceptibilities to atherosclerosis, were fed a chow diet and an atherogenic diet containing taurocholate. Compared with the more atherosclerosis–susceptible C57BL/6 mice, C3H/HeJ mice display resistance to dietary bile acid repression of hepatic PON1 mRNA and decreased high-density lipoprotein cholesterol. Whereas knockout of toll receptor 4 did not affect response to taurocholate, deletion of either FXR or FGFR4 blocked taurocholate repression of PON1 and CYP7A1. FGF19, an activator of FGFR4 expressed in human ileum, decreased expression of both PON1 and CYP7A1 expression by human hepatoma cells. In all of the mice studied, dietary taurocholate increased ileal expression of FGF15, a FXR-inducible murine homologue of human FGF19.
CONCLUSIONS—Hepatic PON1 and CYP7A1 mRNA expression is repressed by bile acids via FXR-mediated induction of FGF15. Thus, the inability of C3H/HeJ mice to display taurocholate repression of PON1 and CYP7A1 mRNAs was not because of a lack of induction of FGF15 but rather signaling events distal to FGF15-FGFR4 association.
• Premise of the study: Sex allocation models assume male and female traits are measured in a common currency, allocation traits show heritability, and tradeoffs between investment in the two sexual ...functions occur. The potential for model predictions and genetic parameters to depend on the currency used is not well understood, despite frequent use of measures not in a common currency.• Methods: We analyzed the relationship between common currency (biomass of carpels, seeds, and stamens) measures and morphological measures (numbers of ovules, seeds, and pollen) in Schiedea salicaria (12–13% females) and S. adamantis (39% females), two closely related gynodioecious species. Additionally, we compared heritabilities and genetic correlations for male and female allocation between these two types of measures.• Key results: Ovule, seed, and pollen number show greater sexual dimorphism in S. adamantis than in S. salicaria. Most but not all morphological traits and analogous biomass traits are highly correlated with a linear relationship. Narrow-sense heritabilities based on the two methods are often similar, but higher for ovule number than carpel mass and lower for anther number than stamen mass in S. adamantis. Neither trait type shows negative genetic correlations between male and female function.• onclusions: Both trait types show greater sexual dimorphism in S. adamantis, and significant heritabilities suggest that morphological traits will continue to evolve with breeding system changes. Although most relationships between morphological and biomass traits are linear, curvilinear relationships for two traits suggest that caution is warranted if morphological and common currency traits are used interchangeably in fitness gain curves.
A family of 3-methoxypoly(ethylene glycol)–vinyl ether–1,2-dioleylglycerol (mPEG-VE-DOG) lipopolymer conjugates, designed on the basis of DFT calculations to possess a wide range of proton ...affinities, was synthesized and tested for their hydrolysis kinetics in neutral and acidic buffers. Extruded ∼100 nm liposomes containing these constructs in ≥90 mol % 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) produced dispersions that retained their calcein cargo for more than 2 days at pH 7.5, but released the encapsulated contents over a wide range of time scales as a function of the electronic properties of the vinyl ether linkage, the solution pH, and the mPEG-VE-DOG composition in the membrane. The in vivo performance of two different 90:10 DOPE:mPEG-VE-DOG compositions was also evaluated for blood circulation time and biodistribution in mice, using 125I-tyraminylinulin as a label. The pharmacokinetic profiles gave a t 1/2 of 7 and 3 h for 90:10 DOPE:ST302 and 90:10 DOPE:ST502, respectively, with the liposomes being cleared predominantly by liver and spleen uptake. The behavior of these DOPE:mPEG-VE-DOG formulations is consistent with their relative rates of vinyl ether hydrolysis, i.e., the more acid-sensitive mPEG-VE-DOG derivatives produced faster leakage rates from DOPE:mPEG-VE-DOG liposomes, but decreased the blood circulation times in mice. These findings suggest that the vinyl ether-based PEG–lipid derivatives are promising agents for stabilizing acid-sensitive DOPE liposomes to produce formulations with a priori control over their pH responsiveness in vitro. Our data also suggest, however, that the same factors that contribute to enhanced acid sensitivity of the DOPE:mPEG-VE-DOG dispersions are also likely responsible for their reduced pharmacokinetic profiles.
We present findings from the inaugural American College of Sports Medicine (ACSM) International Multidisciplinary Roundtable, which was convened to evaluate the evidence for physical activity as a ...means of preventing or modifying the course of NAFLD.
A scoping review was conducted to map the scientific literature and identify key concepts, research gaps, and evidence available to inform clinical practice, policymaking, and research. The scientific evidence demonstrated regular physical activity is associated with decreased risk of NAFLD development. Low physical activity is associated with a greater risk for disease progression and extrahepatic cancer. During routine health care visits, all patients with NAFLD should be screened for and counseled about physical activity benefits, including reduction in liver fat and improvement in body composition, fitness, and quality of life. While most physical activity benefits occur without clinically significant weight loss, evidence remains limited regarding the association between physical activity and liver fibrosis. At least 150 min/wk of moderate or 75 min/wk of vigorous-intensity physical activity are recommended for all patients with NAFLD. If a formal exercise training program is prescribed, aerobic exercise with the addition of resistance training is preferred.
The panel found consistent and compelling evidence that regular physical activity plays an important role in preventing NAFLD and improving intermediate clinical outcomes. Health care, fitness, and public health professionals are strongly encouraged to disseminate the information in this report. Future research should prioritize determining optimal strategies for promoting physical activity among individuals at risk and in those already diagnosed with NAFLD.
Empagliflozin (EMP) is a member of the gliflozin class of drugs used to treat type 2 diabetes mellitus (T2DM). These drugs inhibit the sodium glucose co-transporter 2 (SGLT-2) and facilitate glucose ...disposal via the kidneys. There is considerable interest in the growing evidence that select anti-diabetic drugs such as empagliflozin may have a cardioprotective effect independent of glycemic control manifested as a reduction in the risk of developing a major adverse cardiovascular event (MACE). The mechanism(s) underlying this effect are unknown. To test the hypothesis that the beneficial cardiac effects of EMP may be mediated by enhancing mitochondrial turnover, specifically enhanced mitophagy and mitochondrial biogenesis, we treated 5 day differentiated H9C2 rat ventricular cardiomyocytes with 100nM EMP for 24h. As shown below, we found that EMP increases several markers of mitochondrial mass assessed by western blot. Seahorse respirometry confirmed that this translates to increased basal and maximal respiratory capacity of the cardiomyocyte. Moreover, these findings were associated with increased translocation of PGC-1α to the nucleus suggesting that EMP-mediated mitochondrial biogenesis is PGC-1α-dependent. To determine if increased mitochondrial biogenesis was SGLT-2 receptor mediated we interrogated the protein expression in our differentiated H9C2 cardiomyocytes and in several tissues of the mouse. We detected protein expression in our differentiated H9C2 cardiomyocytes and in mouse heart, liver, adipose, kidney, lung, and spleen. Whether EMP-mediated stimulation of mitochondrial biogenesis is related to SGLT-2 receptor inhibition, or if this process is linked to its ability to improve cardiac function has yet to be determined. Our findings suggest however that a possible mechanism underlying the reduction in MACE associated with EMP treatment may be due in part to its effect on mitochondrial turnover.
Abstract only
Introduction:
To better understand the cardioprotective mechanisms of regular physical activity (PA), we examined its association with plasma bioactive lipids (BAL) and prospective ...cardiovascular disease (CVD) events and evaluated the extent to which BMI might mediate this association.
Hypothesis: 1)
Higher PA associates with a bioactive lipid profile related to lower CVD risk;
2)
BMI mediates the PA-BAL and BAL-CVD associations.
Methods:
Using linear models (adjusted for age, sex, race, smoking, LDL, and total cholesterol), self-reported PA was examined with BAL assayed by an untargeted metabolomics platform in VITAL (N=1032) with validation in JUPITER (N=589). After performing mediation analysis through BMI (same adjustments), we evaluated both BMI-mediated and non-mediated PA-BAL associations with incident CVD using similarly adjusted conditional logistic regression in two nested CVD case-control studies: VITAL-CVD (770 pairs, followed by mediation analysis) and JUPITER-CVD (415 case-control pairs - validation)
Results:
We detected 237 significant PA-BAL associations in VITAL with replication in JUPITER (FDR<.1). Mediation analysis revealed 146 BMI-mediated associations (indirect effect p<.05), of which 53 showed a relationship with incident CVD in VITAL-CVD. Of those, 22 significant CVD-BAL associations were found in JUPITER-CVD (20 from 49 BMI-mediated and 2 from 4 non-BMI-mediated associations in VITAL-CVD). No relationship with CVD was found from the set of PA-BAL associations not mediated by BMI (indirect effect p≥.05). Notably, BALs related to decreased risk of CVD were positively associated with PA and
vice-versa
.
Conclusion:
We identified a signature of 22 PA-related BAL, which were also associated with incident CVD in two independent case-control studies. Although BMI-mediated associations were predominant, non-mediated effects were also detected, implying that more than one pathway may play a role in the PA-CVD relationship.
Glucagon-like peptide 1 receptor agonist (GLP1Ra) and its variants have been shown to protect against cardiac ischemic injury. Less is known about their effects on adverse post-MI LV remodeling. ...Based on our observation that GLP1Ra stimulated mitophagy in H9C2 cardiac cells, we evaluated its effects on post-MI remodeling. Mice underwent permanent coronary artery ligation (PCAL), ensuring remodeling would be independent of changes in infarct size. Vehicle or GLP1Ra (Sigma) were administered i.p. 2h after the infarct and then every other day for a total of 6 doses. LV remodeling was assessed 30 days post-MI via echo. Histology was used to examine immune cell infiltration 7 days post-MI (early phase) via hematoxylin and eosin staining, and fibrosis by Masson’s trichrome after 30 days (late phase). GLP1Ra-treated mice exhibited a marked reduction in immune cell infiltration (A), and fibrosis (B). This corresponded to a significant improvement in ejection fraction (EF) and fractional shortening (FS) (C), although not to the levels of sham-operated mice (EF 60% and FS 30%, data not shown). We assessed the importance of GLP1Ra-induced mitophagy in Parkin KO (PKO) mice. GLP1Ra failed to attenuate adverse remodeling (D and E) and immune cell infiltration (F) in PKO mice implicating the importance of mitophagy as an underlying mechanism. We next determined the effect of GLP1Ra on the activation state of the pyruvate dehydrogenase complex (PDC), which governs substrate utilization. Ischemically injured hearts shift fuel use towards carbohydrate oxidation, which we confirmed in our PCAL model via decreased phosphorylation of the PDC. Post-MI administration of GLP1Ra promoted PDC phosphorylation and thereby restored fatty acid utilization during the early phase of remodeling (G and H). These findings suggest that alterations in cardiac metabolic poise after ischemic injury play a role in adverse remodeling and that stimulation of mitochondrial turnover influences this process.
Abstract only Introduction: Premenopausal women, as well as females in animal studies, have a reduced risk of cardiovascular diseases and a reduced myocardial susceptibility to ischemia/reperfusion ...(I/R) injury. However, with constantly increasing prevalence of obesity, the impact of diet-induced obesity on females remains unclear. Mechanisms of autophagy and mitophagy, differentially regulated between males and females, have been shown to be cardioprotective and impacted under nutritional overload. Hypothesis: Autophagy and mitophagy pathways can be involved in both female cardio protection and deleterious effect of obesity. Methods: Male and female C57Bl/6J mice (n =20 per group) of 8 weeks old were fed a low-fat (LFD, 10% fat) or high-fat (HFD, 60% fat) diet for 12 weeks. At 12 weeks, hearts from mice were studied under basal conditions and after global no-flow ischemia and reperfusion on a Langendorff perfusion system. Results: In both males and females, HFD significantly increases body weight (31.4g vs 48.3g and 22.1g vs 39.9g respectively), fat mass (+200% in males and +300% in females) and blood glucose (+79mg/dl and + 54mg/dl, respectively) (all p<0.01). HFD tends to decrease flow reperfusion after global no-flow ischemia and to increase infarct size (p=0.08 in female and p=0.1 in male, n=5) in both sexes. In males and females, HFD increases pSer757-Ulk1 and decreases Parkin levels under basal conditions (all p<0.006). Moreover, HFD tends to decrease pThr172-AMPK only in females. After I/R, Parkin levels remain lower in HFD groups without sex-difference (p<0.004) but a drastic increase of LC3-II occurs only in females under HFD (p=0.047). Conclusion: All together, these results suggest an impairment of autophagy and mitophagy pathways under HFD. A more drastic change occurs in female mice and may imply a more important response of female mice to HFD, although further studies are needed. However, this result suggests that cardiovascular disease may be more deleterious in women despite their lower cardiovascular risk; additional studies examining sex differences in the response to metabolic syndrome and ischemic heart disease are warranted.
Abstract only Pioglitazone (PIO) and GLP-1R receptor agonist (GLP1Ra) have been shown to be cardioprotective against ischemic cardiac injury. Much less is known about the effects of these agents on ...adverse post-MI LV remodeling. Based on our earlier findings that PIO and a GLP1Ra stimulate mitochondrial turnover, we evaluated the effects of these agents on post-MI remodeling. Lean mice underwent permanent coronary artery ligation (PCAL) to ensure that remodeling would be independent of changes in infarct size. Vehicle, PIO and GLP1Ra (Sigma) were administered i.p. 2h after the infarct and then every other day for a total of 6 doses. Echo and histology (Masson’s trichrome) were used to assess LV remodeling 30 days post-MI (late phase); immune cell infiltration was assessed 7 days after PCAL (early phase) via hematoxylin and eosin (H&E) staining. Both PIO and GLP1Ra were associated with significant improvements in ejection fraction and fractional shortening (A); however, at the dose used, neither drug restored function to that of the sham-operated mice (EF 60% and FS 30%, data not shown). GLP1Ra-treated mice exhibited a marked reduction in immune cell infiltration at 7d after PCAL (B), and fibrosis at 30d (C) compared to vehicle or PIO. While PIO had no effect on immune-cell infiltration and fibrosis, it was effective in attenuating post-MI remodeling. While sharing a common endpoint of attenuating adverse remodeling, the finding that PIO stimulates mitochondrial biogenesis and GLP1Ra induces mitophagy may help explain their disparate findings with respect to early phase remodeling.
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