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

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

Leptin receptor signaling regulates protein synthesis pathways and neuronal differentiation in pluripotent stem cells

The role of leptin receptor (OB-R) signaling in linking pluripotency with growth and development and the consequences of dysfunctional leptin signaling on progression of metabolic disease is poorly understood. Using a global unbiased proteomics approach we report that embryonic fibroblasts (MEFs) carrying the db/db mutation exhibit metabolic abnormalities, while their reprogrammed induced pluripotent stem cells (iPSCs) show altered expression of proteins involved in embryonic development. An upregulation in expression of eukaryotic translation initiation factor 4e (Eif4e) and Stat3 binding to the Eif4e promoter was supported by enhanced protein synthesis in mutant iPSCs. Directed differentiation of db/db iPSCs toward the neuronal lineage showed defects. Gene editing to correct the point mutation in db/db iPSCs using CRISPR-Cas9, restored expression of neuronal markers and protein synthesis while reversing the metabolic defects. These data imply a direct role for OB-R in regulating metabolism in embryonic fibroblasts and key developmental pathways in iPSCs.publishedVersio

IL-17 signaling accelerates the progression of nonalcoholic fatty liver disease in mice

Inflammation plays a central pathogenic role in the pernicious metabolic and end-organ sequelae of obesity. Among these sequelae, nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease in the developed world. The twinned observations that obesity is associated with increased activation of the interleukin (IL)-17 axis and that this axis can regulate liver damage in diverse contexts prompted us to address the role of IL-17RA signaling in the progression of NAFLD. We further examined whether microbe-driven IL-17A regulated NAFLD development and progression. We show here that IL-17RA−/− mice respond to high-fat diet stress with significantly greater weight gain, visceral adiposity, and hepatic steatosis than wild-type controls. However, obesity-driven lipid accumulation was uncoupled from its end-organ consequences in IL-17RA−/− mice, which exhibited decreased steatohepatitis, nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase enzyme expression, and hepatocellular damage. Neutralization of IL-17A significantly reduced obesity-driven hepatocellular damage in wild-type mice. Further, colonization of mice with segmented filamentous bacteria (SFB), a commensal that induces IL-17A production, exacerbated obesity-induced hepatocellular damage. In contrast, SFB depletion protected from obesity-induced hepatocellular damage. Conclusion: These data indicate that obesity-driven activation of the IL-17 axis is central to the development and progression of NAFLD to steatohepatitis and identify the IL-17 pathway as a novel therapeutic target in this condition. (Hepatology 2014;59:1830–1839

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

Dietary Counseling Aimed at Reducing Sugar Intake Yields the Greatest Improvement in Management of Weight and Metabolic Dysfunction in Children with Obesity

Pediatric obesity is a significant public health problem, the negative outcomes of which will challenge individual well-being and societal resources for decades to come. The objective of this study was to determine the effects of dietary counseling on weight management and metabolic abnormalities in children with obesity. One hundred and sixty-five patients aged 2–18 years old were studied over a two and a half year period. Data collected included demographic information, anthropometric assessment, laboratory measurements, and self-reported eating behaviors. Dietary counseling was provided at each visit. The data was analyzed from the first and last visits and the subjects were retrospectively divided into responders and non-responders based on a decrease in their BMI. After receiving dietary guidance, BMI decreased in 44% of the children, and these participants were classified as responders (BMI-R; n = 72). However, BMI did not improve in 56% of the participants, and these were classified as non-responders (BMI-NR; n = 93). At the initial visit, anthropometric measurements and dietary habits were similar between the groups. At the time of the last visit, mean change in BMI was −1.47 (SD 1.31) for BMI-R and +2.40 (SD 9.79) for BMI-NR. Analysis of food intake revealed that BMI-R significantly improved their dietary habits (p = 0.002) by reducing the intake of sugar-sweetened beverages (p = 0.019), processed foods (p = 0.002), sweets (p p = 0.009), as compared with BMI-NR. There was no change in the intake of second helpings, portion sizes, skipping meals, frequency of meals eaten at school, condiment use, intake of fruits and vegetables and consumption of whole grains between the groups. BMI-R also achieved an improvement in fasted glucose (p = 0.021), triglycerides (p p = 0.023), as compared to BMI-NR. In conclusion, children with obesity who were able to decrease their BMI implemented a significant reduction in consumption of foods with high sugar content. Focusing on reducing sugar intake may yield the biggest impact in terms of weight management and the improvement of metabolic abnormalities

Hepatic Natural Killer T-Cell And Cd8+ T-Cell Signatures In Mice With Nonalcoholic Steatohepatitis

Hepatic inflammation is a key pathologic feature of nonalcoholic steatohepatitis (NASH). Natural killer T (NKT) cells and clusters of differentiation (CD)8+ T-cells are known to play an important role in obesity-related adipose tissue inflammation. We hypothesized that these same inflammatory phenotypes would be present in progressive NASH. We used a previously established high-fat high-carbohydrate (HFHC) murine obesogenic diet model of progressive NASH to investigate the role of NKT cells and CD8+ T-cells in C57Bl6/J mice. To better understand the impact of these cell populations, CD1d-deficient and CD8+ T-cell-depleted mice were subjected to an HFHC diet for 16 weeks. C57Bl6/J mice fed an HFHC diet had increased body weight, liver triglyceride content, serum alanine aminotransferase levels, and increased NKT-cell and CD8+ T-cell infiltration in the liver. In addition, human liver sections from patients with NASH showed increased CD8+ T-cells. In comparison, CD1d-deficient and CD8 T-cell-depleted mice fed an HFHC diet had a lower hepatic triglyceride content, lower alanine aminotransferase levels, lower activated resident macrophages and infiltrating macrophages, improved nonalcoholic fatty liver disease activity scores, and reduced α-smooth muscle actin, collagen type 1 alpha 1, and collagen type 1 alpha 2 messenger RNA expression. Further, while CD1d-deficient mice were protected against weight gain on the HFHC diet, CD8 T-cell-depleted mice gained weight on the HFHC diet. Conclusion: We found that NASH has an immunological signature that includes hepatic infiltrating NKT and CD8+ T-cells. Depletion of these cells resulted in reduced NASH progression and thus presents novel therapeutic avenues for the treatment of NASH. (Hepatology Communications 2017;1:299–310)

Hepatic natural killer T‐cell and CD8+ T‐cell signatures in mice with nonalcoholic steatohepatitis

Hepatic inflammation is a key pathologic feature of nonalcoholic steatohepatitis (NASH). Natural killer T (NKT) cells and clusters of differentiation (CD)8+ T‐cells are known to play an important role in obesity‐related adipose tissue inflammation. We hypothesized that these same inflammatory phenotypes would be present in progressive NASH. We used a previously established high‐fat high‐carbohydrate (HFHC) murine obesogenic diet model of progressive NASH to investigate the role of NKT cells and CD8+ T‐cells in C57Bl6/J mice. To better understand the impact of these cell populations, CD1d‐deficient and CD8+ T‐cell‐depleted mice were subjected to an HFHC diet for 16 weeks. C57Bl6/J mice fed an HFHC diet had increased body weight, liver triglyceride content, serum alanine aminotransferase levels, and increased NKT‐cell and CD8+ T‐cell infiltration in the liver. In addition, human liver sections from patients with NASH showed increased CD8+ T‐cells. In comparison, CD1d‐deficient and CD8 T‐cell‐depleted mice fed an HFHC diet had a lower hepatic triglyceride content, lower alanine aminotransferase levels, lower activated resident macrophages and infiltrating macrophages, improved nonalcoholic fatty liver disease activity scores, and reduced α‐smooth muscle actin, collagen type 1 alpha 1, and collagen type 1 alpha 2 messenger RNA expression. Further, while CD1d‐deficient mice were protected against weight gain on the HFHC diet, CD8 T‐cell‐depleted mice gained weight on the HFHC diet. Conclusion:: We found that NASH has an immunological signature that includes hepatic infiltrating NKT and CD8+ T‐cells. Depletion of these cells resulted in reduced NASH progression and thus presents novel therapeutic avenues for the treatment of NASH. (Hepatology Communications 2017;1:299–310