Search

Since organoids were developed 15 years ago, they are now in their adolescence as a research tool. The ability to generate 'tissue in a dish' has created enormous opportunities for biomedical research. We examine the contributions that hepatic organoids have made to three areas of liver research: as a source of cells and tissue for basic research, for drug discovery and drug safety testing, and for understanding disease pathobiology. We discuss the features that enable hepatic organoids to provide useful models for human liver diseases and identify four types of advances that will enable them to become a mature (i.e., adult) research tool over the next 5 years. During this period, advances in single‐cell RNA sequencing and CRISPR technologies coupled with improved hepatic organoid methodology, which enables them to have a wider range of cell types that are present in liver and to be grown in microwells, will generate discoveries that will dramatically advance our understanding of liver development and the pathogenesis of liver diseases. It will generate also new approaches for treating liver fibrosis, which remains a major public health problem with few treatment options. [ABSTRACT FROM AUTHOR]

The nuclear receptors PPAR[alpha] (encoded by NR1C1) and farnesoid X receptor (FXR, encoded by NR1H4) are activated in the liver in the fasted and fed state, respectively. PPAR[alpha] activation induces fatty acid oxidation, while FXR controls bile acid homeostasis, but both nuclear receptors also regulate numerous other metabolic pathways relevant to liver energy balance. Here we review evidence that they function coordinately to control key nutrient pathways, including fatty acid oxidation and gluconeogenesis in the fasted state and lipogenesis and glycolysis in the fed state. We have also recently reported that these receptors have mutually antagonistic impacts on autophagy, which is induced by PPAR[alpha] but suppressed by FXR. Secretion of multiple blood proteins is a major drain on liver energy and nutrient resources, and we present preliminary evidence that the liver secretome may be directly suppressed by PPAR[alpha], but induced by FXR. Finally, previous studies demonstrated a striking deficiency in bile acid levels in malnourished mice that is consistent with results in malnourished children. We present evidence that hepatic targets of PPAR[alpha] and FXR are dysregulated in chronic undernutrition. We conclude that PPAR[alpha] and FXR function coordinately to integrate liver energy balance., Introduction The liver is a central mediator of feeding and fasting transitions, pivoting from carbohydrate-based energy accumulation in the fed state to fatty acid oxidation-dependent (FAO-dependent) energy utilization in the [...]

The present study aimed to evaluate the effect of trigonelline (TRG) on the hepatic complications associated with high-fat high-fructose (HFHF) diet-induced insulin resistance (IR) in rats. IR was induced by giving a saturated fat diet and 10% fructose in drinking water to rats for 8 weeks. Insulin-resistant rats were orally treated with TRG (50 and 100 mg/kg), sitagliptin (SIT; 5 mg/kg), or a combination of TRG (50 mg/kg) and SIT (5 mg/kg) for 14 days. Liver homogenates were used for assessment of hepatic lipids, oxidative stress biomarkers, and inflammatory cytokines. Histopathological and DNA cytometry examinations were carried out for hepatic and pancreatic tissues. Hepatic tissues were examined using Fourier-transform infrared spectroscopy for assessment of any molecular changes. Results of the present study revealed that oral treatment of insulin-resistant rats with TRG or TRG in combination with SIT significantly decreased homeostatic model assessment of IR, hepatic lipids, oxidative stress biomarkers, and the inflammatory cytokines. TRG or TRG in combination with SIT ameliorated the histopathological, DNA cytometry, and molecular alterations induced by a HFHF diet. Finally, it can be concluded that TRG has beneficial effects on the hepatic complications associated with IR due to its hypoglycemic effect and antioxidant potential. Key words: trigonelline, sitagliptin, insulin resistance, liver, molecular alterations. L'etude presente visait a evaluer l'effet de la trigonelline (TRG) sur les complications hepatiques associees a la resistance a l'insuline (RI) induite par une diete riche en gras et riche en fructose (RGRF) chez le rat. La RI a ete induite par l'administration d'une diete riche en gras satures et 10 % de fructose a l'eau de consommation des rats pendant 8 semaines. Les rats resistants a l'insuline ont ete traites par voie orale avec la TRG (50 et 100 mg/kg), la sitagliptine (SIT; 5 mg/kg) ou une combinaison de TRG (50 mg/kg) et de SIT (5 mg/kg) pendant 14 jours. Des homogenats de foie ont ete utilises pour evaluer les lipides hepatiques, les biomarqueurs du stress oxydant et les cytokines inflammatoires. Des examens histopathologiques et en cytometrie de l'ADN ont ete effectues sur les tissus hepatiques et pancreatiques. Les tissus hepatiques ont ete examines par spectroscopie infrarouge par transformee de Fourier afin d'evaluer tout changement moleculaire. Les resultats de la presente etude ont revele que le traitement oral des rats resistants a l'insuline par la TRG ou par la TRG combinee a la SIT diminuait significativement l'indice HOMA-IR (<>), les lipides hepatiques, les biomarqueurs de stress oxydant et les cytokines inflammatoires. La TRG ou la TRG combinee a la SIT amelioraient les changements histopathologiques, en cytometrie de l'ADN et moleculaires induits par une diete RGRF. Finalement, on peut conclure que la TRG exerce des effets benefiques sur les complications hepatiques associees a la RI a cause de son effet hypoglycemiant et son potentiel antioxydant. [Traduit par la Redaction] Mots-cles : trigonelline, sitagliptine, resistance a l'insuline, foie, changements moleculaires., Introduction Insulin resistance (IR) is a metabolic disorder that plays a major role in the pathophysiology of the most common human diseases, such as diabetes mellitus (DM), hypertension, obesity, dyslipidemia, [...]

Hepatic glucose production (HGP) is a key determinant of glucose homeostasis. Glucagon binding to its cognate seven-transmembrane [G.sub.s]-coupled receptor in hepatocytes stimulates cAMP production, resulting in increased HGP. In this issue of the JCI, Rossi and colleagues tested the hypothesis that activation of hepatic [G.sub.i]-coupled receptors, which should inhibit cAMP production, would oppose the cAMP-inducing action of glucagon and thereby decrease HGP. Surprisingly, however, the opposite occurred: activation of [G.sub.i] signaling increased HGP via a novel mechanism, while inhibition of [G.sub.i] signaling reduced HGP. These results define a new physiologic role for hepatic [G.sub.i] signaling and identify a potential therapeutic target for HGP regulation., Regulation of hepatic glucose production Appropriate regulation of hepatic glucose production (HGP) is critical for glucose homeostasis under conditions that range from high glucose demand, such as prolonged fasting, to [...]

Common obesity-associated hepatic steatosis (nonalcoholic fatty liver disease (NAFLD)) and insulin resistance are mainly caused by dysfunctional adipose tissue. This adipose tissue dysfunction leads to increased delivery of NEFA and glycerol to the liver that (i) drives hepatic gluconeogenesis and (ii) facilitates the accumulation of lipids and insulin signaling inhibiting lipid intermediates. Dysfunctional adipose tissue can be caused by impaired lipid storage (overflow hypothesis, characterized by large visceral adipocytes) or increased lipolysis (due to impaired postprandial suppression of lipolysis in inflamed, insulin-resistant adipocytes). In line with the adipose tissue expandability hypothesis the amount and distribution of adipose tissue correlate with its dysfunction and thus with liver fat. This relationship is however modified by endocrine effects on lipid storage and lipolysis as well as dietary effects on hepatic lipogenesis and lipid oxidation. The association between body composition characteristics like visceral obesity or fat cell size and ectopic liver fat is modified by these influences. Phenotyping obesity according to metabolic risk should integrate body composition characteristics, endocrine parameters and information on diet., Author(s): Anja Bosy-Westphal [sup.1] , Wiebke Braun [sup.1] , Viktoria Albrecht [sup.1] , Manfred J. Müller [sup.1] Author Affiliations: (1) Institute for Human Nutrition and Food Science, Christian-Albrechts-University Kiel, Kiel, [...]

Increases in biomechanical forces in the liver's blood vessels have now been shown to activate two mechanosensitive proteins. The proteins trigger blood-vessel cells to deploy regenerative factors that drive liver growth.Mechanical forces on endothelial cells promote hepatocyte proliferation., Author(s): Sina Y. Rabbany, Shahin RafiiAuthor Affiliations:Blood flow forces liver growth Mechanosensing in the liver depends on the amount of blood delivered by the portal vein and the hepatic artery, [...]