Evolving Role for Pharmacotherapy in NAFLD/NASH

Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent, dynamic disease that occurs across the age spectrum and can lead to cirrhosis and hepatocellular carcinoma. There are currently no US Food and Drug Administration (FDA) approved treatments for NAFLD; however, this is a field of active research. This review summarizes emerging pharmacotherapies for the treatment of adult and pediatric NAFLD. Investigated pharmacotherapies predominantly target bile acid signaling, insulin resistance, and lipid handling within the liver. Three drugs have gone on to phase III trials for which results are available. Of those, obeticholic acid is the single agent that demonstrates promise according to the interim analyses of the REGENERATE trial. Obeticholic acid showed reduction of fibrosis in adults with nonalcoholic steatohepatitis (NASH) taking 25 mg daily for 18 months (n = 931, reduction in fibrosis in 25% vs. 12% placebo, P \u3c 0.01). Ongoing phase III trials include REGENERATE and MAESTRO-NASH, which investigates thyroid hormone receptor-β agonist MGL-3196. Outcomes of promising phase II trials in adults with NASH are also available and those have investigated agents, including the fibroblast growth factor (FGF)19 analogue NGM282, the GLP1 agonist liraglutide, the FGF21 analogue Pegbelfermin, the sodium glucose co-transporter 2 inhibitor Empagliflozin, the ketohexokinase inhibitor PF-06835919, the acetyl-coenzyme A carboxylase inhibitor GS-0976, and the chemokine receptor antagonist Cenicriviroc. Completed and ongoing clinical trials emphasize the need for a more nuanced understanding of the phenotypes of subgroups within NAFLD that may respond to an individualized approach to pharmacotherapy

Editorial:FGF21 as a therapeutic target for obesity and insulin resistance: from rodent models to humans

Obesity is a global pandemic that requires the urgent development of therapies and prevention strategies. To define new pharmacologic therapies or nutritional approaches it is mandatory to find new targets. Fibroblast growth factor 21 (FGF21) is considered a potential target to treat obesity, due to its favorable metabolic activity, signalling pathways and regulatory mechanisms. It is well-documented that FGF21 is induced by a wide range of biological stress conditions and a key signal that communicates and coordinates the physiologic response to restore the metabolic homeostasis in different tissues (1). FGF21 is elevated in pathological conditions such as obesity, insulin resistance, or fatty liver disease where an impairment of its signalling has been described (2). On the other hand, FGF21 analogues tested in overweight/obese patients with type 2 diabetes or NAFLD/NASH can reduce dyslipidaemia and steatosis, but improvements in glycaemic control or body weight were not globally restored (3). This suggests that pharmacologic effects of FGF21 are different from its physiological effects. In this Research Topic “FGF21 as a therapeutic target for obesity and insulin resistance: from rodent models to humans”, we include publications related to new advances involving FGF21, its signalling pathway, and its potential as a target to treat obesityinfo:eu-repo/semantics/publishedVersio

Direct cost variance analysis of peroral endoscopic myotomy vs Heller myotomy for management of achalasia: A tertiary referral center experience

BACKGROUND: Laparoscopic Heller myotomy (LHM) has been the traditional surgical treatment for achalasia. Recently, peroral endoscopic myotomy (POEM) has demonstrated similar clinical outcomes with shorter procedure times. Studies comparing the direct cost-effectiveness of POEM AIM: To compare costs of POEM METHODS: This retrospective chart review aimed to compare the outcomes and cost of clinical care between patients who underwent POEM and LHM procedures for achalasia. The study was conducted at a tertiary academic center from January 2019 to December 2020. Clinical outcomes, including post-operative Eckardt scores and adverse events, were assessed and compared between the two groups. Direct cost variance analysis was utilized to evaluate the cost of clinical care incurred by patients undergoing POEM in the year preceding the procedure, during the index admission, and one year post-procedure, in comparison to patients undergoing LHM. RESULTS: Of 30 patients were included (15 POEM and 15 LHM) in the study. Patients in the POEM group had a mean Eckardt score of 0.5 ± 0.5 post-procedure, which was no different from patients in the LHM group (0.7 ± 0.6, CONCLUSION: Despite similar clinical outcomes, the cost of the index procedure admission for POEM was significantly lower than for LHM. The difference was primarily related to shorter time increments utilized in the operating room during the index procedure, and shorter length of hospital stay following POEM

Supporting self-regulated learning

Self-regulated learning (SRL) competences are crucial for lifelong learning. Their cultivation requires the right balance between freedom and guidance during the learning processes. Current learning systems and approaches, such as personal learning environments, give overwhelming freedom, but also let weak learners alone. Other systems, such as learning management systems or adaptive systems, tend to institutionalise learners too much, which does not support the development of SRL competences. This chapter presents possibilities and approaches to support SRL by the use of technology. After discussing the theoretical background of SRL and related technologies, a formal framework is presented that describes the SRL process, related competences, and guidelines. Furthermore, a variety of methods is presented, how learners can be supported to learn in a self-regulated way

Insulin Concentration Modulates Hepatic Lipid Accumulation in Mice in Part via Transcriptional Regulation of Fatty Acid Transport Proteins

Fatty liver disease (FLD) is commonly associated with insulin resistance and obesity, but interestingly it is also observed at low insulin states, such as prolonged fasting. Thus, we asked whether insulin is an independent modulator of hepatic lipid accumulation.In mice we induced, hypo- and hyperinsulinemia associated FLD by diet induced obesity and streptozotocin treatment, respectively. The mechanism of free fatty acid induced steatosis was studied in cell culture with mouse liver cells under different insulin concentrations, pharmacological phosphoinositol-3-kinase (PI3K) inhibition and siRNA targeted gene knock-down. We found with in vivo and in vitro models that lipid storage is increased, as expected, in both hypo- and hyperinsulinemic states, and that it is mediated by signaling through either insulin receptor substrate (IRS) 1 or 2. As previously reported, IRS-1 was up-regulated at high insulin concentrations, while IRS-2 was increased at low levels of insulin concentration. Relative increase in either of these insulin substrates, was associated with an increase in liver-specific fatty acid transport proteins (FATP) 2&5, and increased lipid storage. Furthermore, utilizing pharmacological PI3K inhibition we found that the IRS-PI3K pathway was necessary for lipogenesis, while FATP responses were mediated via IRS signaling. Data from additional siRNA experiments showed that knock-down of IRSs impacted FATP levels.States of perturbed insulin signaling (low-insulin or high-insulin) both lead to increased hepatic lipid storage via FATP and IRS signaling. These novel findings offer a common mechanism of FLD pathogenesis in states of both inadequate (prolonged fasting) and ineffective (obesity) insulin signaling

Modulation of hepatic inflammation and energy-sensing pathways in the rat liver by high-fructose diet and chronic stress

Purpose High-fructose consumption and chronic stress are both associated with metabolic inflammation and insulin resistance. Recently, disturbed activity of energy sensor AMP-activated protein kinase (AMPK) was recognized as mediator between nutrient-induced stress and inflammation. Thus, we analyzed the effects of high-fructose diet, alone or in combination with chronic stress, on glucose homeostasis, inflammation and expression of energy sensing proteins in the rat liver. Methods In male Wistar rats exposed to 9-week 20% fructose diet and/or 4-week chronic unpredictable stress we measured plasma and hepatic corticosterone level, indicators of glucose homeostasis and lipid metabolism, hepatic inflammation (pro- and anti-inflammatory cytokine levels, Toll-like receptor 4, NLRP3, activation of NF kappa B, JNK and ERK pathways) and levels of energy-sensing proteins AMPK, SIRT1 and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha). Results High-fructose diet led to glucose intolerance, activation of NF kappa B and JNK pathways and increased intrahepatic IL-1 beta, TNF alpha and inhibitory phosphorylation of insulin receptor substrate 1 on Ser(307). It also decreased phospho-AMPK/AMPK ratio and increased SIRT1 expression. Stress alone increased plasma and hepatic corticosterone but did not influence glucose tolerance, nor hepatic inflammatory or energy-sensing proteins. After the combined treatment, hepatic corticosterone was increased, glucose tolerance remained preserved, while hepatic inflammation was partially prevented despite decreased AMPK activity. Conclusion High-fructose diet resulted in glucose intolerance, hepatic inflammation, decreased AMPK activity and reduced insulin sensitivity. Chronic stress alone did not exert such effects, but when applied together with high-fructose diet it could partially prevent fructose-induced inflammation, presumably due to increased hepatic glucocorticoids

Risk factors for human cutaneous anthrax outbreaks in the hot-spot districts of Northern Tanzania: an unmatched case control study

Royal Society of Open Science, 2018; 5: 180479Bacillus anthracis is an aerobic, Gram-positive and sporeforming bacterium, which causes anthrax in herbivores. Humans get infected after coming into contact with infected animals’ products. An unmatched case–control study was conducted to identify the importance of demographic, biological and/or behavioural factors associated with human cutaneous anthrax outbreaks in the hotspot areas of Northern Tanzania. A semi-structured questionnaire was administered to both cases and controls. The age range of participants was 1–80 years with a median age of 32 years. In the younger group (1–20 years), the odds of being infected were 25 times higher in the exposed group compared to the unexposed group (OR¼ 25, 95% CI ¼ 1.5–410). By contrast, the odds of exposure in the old group ( 20 years) were three times lower in the exposed group compared to the unexposed group (OR ¼ 3.2, 95% CI ¼ 1.28–8.00). Demographic characteristics, sleeping on animal’s skins, contacting with infected carcasses through skinning and butchering, and not having formal education were linked to exposure for anthrax infection. Hence, a One Health approach is inevitable for the prevention and control of anthrax outbreaks in the hotspot areas of Northern Tanzania.The World Ban