☆ 4.7 Review

A new perspective on NAFLD: Focusing on the crosstalk between peroxisome proliferator-activated receptor alpha (PPARα) and farnesoid X receptor (FXR)

BIOMEDICINE & PHARMACOTHERAPY (2022)

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Article Endocrinology & Metabolism

Hepatic CPT1A Facilitates Liver Adipose Cross Talk via Induction of FGF21 in Mice

Wei Sun et al.

Summary: This study reveals that deficiency of hepatic CPT1A protects against high-fat diet-induced liver damage and enhances adipose browning. Activation of the peroxisome proliferator-activated receptor alpha-fibroblast growth factor 21 (FGF21) axis in the liver contributes to the improved metabolic state.

DIABETES (2022)

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Article Pharmacology & Pharmacy

Chiglitazar: First Approval

Emma D. Deeks

Summary: Chiglitazar, an orally administered small-molecule agonist of PPARs, has been approved in China for the treatment of type 2 diabetes and is undergoing phase 2 clinical development for non-alcoholic steatohepatitis.

DRUGS (2022)

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Article Gastroenterology & Hepatology

Novel therapeutic targets for cholestatic and fatty liver disease

Michael Trauner et al.

Summary: Cholestatic and non-alcoholic fatty liver disease have shared pathophysiological mechanisms that can be targeted for intervention through novel therapeutic concepts. Nuclear receptors play a crucial role in the treatment of these diseases, with high affinity therapeutic ligands being developed for specific or multiple isoforms. In addition, other therapeutic approaches targeting inflammation and fibrosis directly are also available. Combination strategies that target metabolic disturbances, inflammation, and fibrosis may be necessary for successful treatment of these complex disorders.

GUT (2022)

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Review Gastroenterology & Hepatology

Role of bile acids and their receptors in gastrointestinal and hepatic pathophysiology

Claudia D. Fuchs et al.

Summary: Bile acids play a crucial role in regulating metabolism and homeostasis, and their disrupted balance can contribute to gastrointestinal and liver diseases. Targeting bile acid pathways may provide novel treatment strategies for these disorders.

NATURE REVIEWS GASTROENTEROLOGY & HEPATOLOGY (2022)

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Editorial Material Gastroenterology & Hepatology

Saroglitazar, a PPAR-α/γ Agonist, for Treatment of Nonalcoholic Fatty Liver Disease: A Randomized Controlled Double-Blind Phase 2 Trial

Manas Kumar Panigrahi et al.

JOURNAL OF CLINICAL AND EXPERIMENTAL HEPATOLOGY (2022)

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Review Cell Biology

Transcriptional Regulation of Hepatic Autophagy by Nuclear Receptors

Eun Young Kim et al.

Summary: Autophagy is an important cellular process involved in the degradation of cellular components and dysfunctions in autophagy are associated with various diseases. Nuclear receptors, as transcription factors, play a role in regulating autophagy and can be utilized for the treatment of liver diseases.

CELLS (2022)

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Article Biochemistry & Molecular Biology

Pharmacotherapy for Non-Alcoholic Fatty Liver Disease: Emerging Targets and Drug Candidates

Veronika A. Prikhodko et al.

Summary: This paper provides an update on the rapidly changing therapeutic landscape of non-alcoholic fatty liver disease (NAFLD). It highlights the major novel approaches to the treatment of this disease and reviews the current status of drug discovery and development pipeline, focusing on recent evidence from clinical trials.

BIOMEDICINES (2022)

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Review Chemistry, Multidisciplinary

Bile acid and receptors: biology and drug discovery for nonalcoholic fatty liver disease

Ting-ying Jiao et al.

Summary: Nonalcoholic fatty liver disease (NAFLD), characterized by lipid accumulation in liver cells, has become the primary cause of chronic liver diseases worldwide. The progression of NAFLD to nonalcoholic steatohepatitis (NASH) is strongly related to multiple metabolic disorders and diseases. Disturbances in bile acid metabolism play a significant role in NASH pathogenesis, and bile acid receptors are considered attractive targets for NASH treatment.

ACTA PHARMACOLOGICA SINICA (2022)

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Review Chemistry, Multidisciplinary

FXR: structures, biology, and drug development for NASH and fibrosis diseases

Si-yu Tian et al.

Summary: The nuclear receptor FXR plays an essential role in maintaining bile acid, glucose, and lipid levels, and is associated with diseases such as obesity and type 2 diabetes. FXR has potential as a therapeutic drug target for enterohepatic diseases, but currently only obeticholic acid (OCA) is approved for primary biliary cholangitis (PBC) treatment.

ACTA PHARMACOLOGICA SINICA (2022)

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Article Biochemistry & Molecular Biology

Nuclear Receptors Linking Metabolism, Inflammation, and Fibrosis in Nonalcoholic Fatty Liver Disease

Tobias Puengel et al.

Summary: Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are chronic liver diseases that can lead to end-stage liver disease and hepatocellular carcinoma (HCC) worldwide. The metabolic syndrome is closely linked to NAFLD, and comorbidities such as type 2 diabetes, obesity, and insulin resistance worsen liver disease, while NAFLD increases cardiovascular risk in affected patients. Therapeutic strategies targeting multiple drug targets or drugs with multiple mechanisms of actions are needed for effective treatment.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2022)

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Review Biochemistry & Molecular Biology

Molecular Basis of Bile Acid-FXR-FGF15/19 Signaling Axis

Takeshi Katafuchi et al.

Summary: Bile acids have detergent and hormone-like properties. FXR and FGF15/19 are considered as potential therapeutic targets for metabolic syndrome and cholestatic diseases.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2022)

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Article Gastroenterology & Hepatology

Non-invasive evaluation of response to obeticholic acid in patients with NASH: Results from the REGENERATE study

Mary E. Rinella et al.

Summary: Non-invasive tests (NITs) have potential applications in evaluating fibrosis and treatment response in patients with non-alcoholic steatohepatitis (NASH). Treatment with obeticholic acid (OCA) can lead to reduced levels of alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyltransferase, as well as improvements in Fibrosis-4, FibroTest, FibroMeter, and FibroScan-AST scores.

JOURNAL OF HEPATOLOGY (2022)

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Article Gastroenterology & Hepatology

EDP-305 in patients with NASH: A phase II double-blind placebo-controlled dose-ranging study

Vlad Ratziu et al.

Summary: EDP-305 reduces ALT levels and liver fat content in patients with NASH, supporting the need for a longer-term trial to evaluate histological endpoints.

JOURNAL OF HEPATOLOGY (2022)

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Article Cell Biology

Enterohepatic and non-canonical roles of farnesoid X receptor in controlling lipid and glucose metabolism

Weinan Zhou et al.

Summary: This review examines the classical and non-canonical tissue-specific roles of FXR in regulating lipids and glucose homeostasis, highlighting the significance of FXR signaling in modulating metabolic processes. It also emphasizes that tissue-specific modulation of FXR may be the key to overcoming some of the adverse clinical effects.

MOLECULAR AND CELLULAR ENDOCRINOLOGY (2022)

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Article Cell Biology

Fibroblast growth factor 15/19 expression, regulation, and function: An overview

Greg Guthrie et al.

Summary: This review summarizes the current literature on the protein FGF19, its target receptors, and the biological pathways they target through unique signaling cascades.

MOLECULAR AND CELLULAR ENDOCRINOLOGY (2022)

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Article Cell Biology

Discovery of farnesoid X receptor and its role in bile acid metabolism

John Y. L. Chiang et al.

Summary: This article introduces the discovery of FXR as a regulator of bile acid metabolism and a metabolic regulator of lipid, glucose, and energy homeostasis. It also provides an update on FXR functions in the gut-to-liver axis and the use of drug therapies targeting bile acids and FXR for the treatment of liver metabolic diseases.

MOLECULAR AND CELLULAR ENDOCRINOLOGY (2022)

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Review Cell Biology

Transcriptional control of energy metabolism by nuclear receptors

Charlotte Scholtes et al.

Summary: Nuclear receptors are transcription factors that regulate metabolic genes by transducing hormonal, nutrient, metabolite, and redox signals. They play a central role in the transcriptional control of energy metabolism and maintain cellular energy homeostasis by adapting gene expression to changing energetic demands. Nuclear receptors must cooperate with other factors, integrate signals from key metabolic pathways, and synchronize their activities with the biological clock to orchestrate a large ensemble of input signals.

NATURE REVIEWS MOLECULAR CELL BIOLOGY (2022)

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Review Immunology

Bile acids and their receptors: modulators and therapeutic targets in liver inflammation

Anna Bertolini et al.

Summary: Bile acids not only play a role in digestion and absorption, but also have potential therapeutic value in regulating metabolism and immune function for the treatment of liver diseases.

SEMINARS IN IMMUNOPATHOLOGY (2022)

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Article Biochemistry & Molecular Biology

Emerging Role of Nuclear Receptors for the Treatment of NAFLD and NASH

Ryan D. Welch et al.

Summary: Non-alcoholic fatty liver (NAFLD) is a metabolic pandemic linked to a collection of metabolic diseases. Nuclear receptors are key regulators of metabolism, and targeting them for NAFLD treatment is promising. Several compounds, including Cilofexor, thiazolidinediones, and Saroglitazar, are currently undergoing clinical trials.

METABOLITES (2022)

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Review Biology

PPAR Alpha as a Metabolic Modulator of the Liver: Role in the Pathogenesis of Nonalcoholic Steatohepatitis (NASH)

Simona Todisco et al.

Summary: Non-alcoholic steatohepatitis (NASH) is a serious transformation from simple steatosis to inflammation and hepatic injury. Profound metabolic dysregulations are associated with NASH, and the peroxisomal-proliferator-activated receptor alpha (PPAR alpha) plays a key role in its pathogenesis. However, many aspects of NASH have not yet been fully clarified.

BIOLOGY-BASEL (2022)

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Review Gastroenterology & Hepatology

Review: Vascular effects of PPARs in the context of NASH

Sergi Guixe-Muntet et al.

Summary: This review summarizes and discusses the pathobiological role of PPARs in cardiovascular diseases, with a special focus on their impact and therapeutic potential in NAFLD and NASH. The importance of evaluating cardiovascular disease in the context of NASH trials is emphasized.

ALIMENTARY PHARMACOLOGY & THERAPEUTICS (2022)

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Article Biochemistry & Molecular Biology

Clinically Relevant Dose of Pemafibrate, a Novel Selective Peroxisome Proliferator-Activated Receptor α Modulator (SPPARMα), Lowers Serum Triglyceride Levels by Targeting Hepatic PPARα in Mice

Zhe Zhang et al.

Summary: Pemafibrate (PEM) is a novel lipid-lowering drug that can efficiently reduce serum triglyceride (TG) levels and increase fibroblast growth factor 21 (FGF21) without causing hepatotoxicity in mice when used at a clinically relevant dose. It binds to peroxisome proliferator-activated receptor alpha (PPAR alpha) and activates it specifically in the liver, leading to enhanced fatty acid uptake and beta-oxidation.

BIOMEDICINES (2022)

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Review Gastroenterology & Hepatology

Multiple Parallel Hits Hypothesis in Nonalcoholic Fatty Liver Disease: Revisited After a Decade

Herbert Tilg et al.

HEPATOLOGY (2021)

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Article Cell Biology

Carbohydrate response element-binding protein regulates lipid metabolism via mTOR complex1 in diabetic nephropathy

Nan Chen et al.

Summary: The lack of ChREBP significantly improves renal injury and reduces lipid deposition in diabetic kidneys, potentially through inhibiting mTORC1 activity. Additionally, ChREBP deficiency can regulate the expression of a range of related genes in diabetic kidneys.

JOURNAL OF CELLULAR PHYSIOLOGY (2021)

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Review Gastroenterology & Hepatology

Nonalcoholic steatohepatitis: the role of peroxisome proliferator-activated receptors

Sven Francque et al.

Summary: The global epidemic of obesity is associated with serious health consequences, including NAFLD, which can progress to liver fibrosis and cirrhosis. NAFLD is a systemic disease affecting multiple organs, with a complex pathomechanism involving PPARs as key regulators.

NATURE REVIEWS GASTROENTEROLOGY & HEPATOLOGY (2021)

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Article Medicine, General & Internal

Open-label phase II study evaluating safety and efficacy of the non-steroidal farnesoid X receptor agonist PX-104 in non-alcoholic fatty liver disease

Stefan Traussnigg et al.

Summary: In non-diabetic NAFLD patients, the non-steroidal FXR agonist PX-104 improved insulin sensitivity and liver enzymes after 4 weeks of treatment. While hepatic steatosis and other measures did not change, alterations in fecal BAs and gut microbiota warrant further investigation.

WIENER KLINISCHE WOCHENSCHRIFT (2021)

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Article Biochemistry & Molecular Biology

SIRT6 controls hepatic lipogenesis by suppressing LXR, ChREBP, and SREBP1

Chaoyu Zhu et al.

Summary: The study identified that the lack of Sirt6 in the liver leads to more severe fatty liver disease and affects the activities of carbohydrate response element binding protein and sterol regulatory element binding protein 1. It was found that Sirt6 can suppress metabolic regulators in the liver through direct deacetylation.

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE (2021)

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Review Gastroenterology & Hepatology

Targeting the Four Pillars of Enterohepatic Bile Salt Cycling; Lessons From Genetics and Pharmacology

Roni F. Kunst et al.

Summary: Bile salts are essential for lipid homeostasis and can be both culprits and potential remedies in gut or liver disorders. Efficient transporters mediate the uptake and efflux of bile salts, ensuring their enterohepatic circulation. Deficiencies in key transporters can lead to pathological conditions, and targeting these pathways may offer new therapeutic opportunities.

HEPATOLOGY (2021)

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Letter Gastroenterology & Hepatology

A Phase 2 Double Blinded, Randomized Controlled Trial of Saroglitazar in Patients With Nonalcoholic Steatohepatitis

Mohammad Shadab Siddiqui et al.

CLINICAL GASTROENTEROLOGY AND HEPATOLOGY (2021)

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Review Physiology

Ceramides in Metabolism: Key Lipotoxic Players

Bhagirath Chaurasia et al.

Summary: The review discusses the impact of lipid metabolites like ceramides on metabolic diseases and the potential therapeutic approaches to combat them.

ANNUAL REVIEW OF PHYSIOLOGY, VOL 83 (2021)

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Article Food Science & Technology

Echinacoside ameliorates alcohol-induced oxidative stress and hepatic steatosis by affecting SREBP1c/FASN pathway via PPARα

Zhi Tao et al.

Summary: The study findings suggest that ECH may protect against ethanol-induced liver injuries by alleviating oxidative stress and hepatic steatosis through affecting the SREBP-1c/FASN pathway via PPAR-alpha. This indicates the potential of ECH in safeguarding the liver from damage caused by ethanol.

FOOD AND CHEMICAL TOXICOLOGY (2021)

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Article Medicine, General & Internal

A Randomized, Controlled Trial of the Pan-PPAR Agonist Lanifibranor in NASH

Sven M. Francque et al.

Summary: In a randomized trial, the pan-PPAR agonist Lanifibranor showed significant improvement in histologic features of NASH at a dose of 1200 mg. However, adverse events such as weight gain, anemia, peripheral edema, diarrhea, and nausea were more common with Lanifibranor compared to placebo.

NEW ENGLAND JOURNAL OF MEDICINE (2021)

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Article Gastroenterology & Hepatology

Gastric Bypass Increases Circulating Bile Acids and Activates Hepatic Farnesoid X Receptor (FXR) but Requires Intact Peroxisome Proliferator Activator Receptor Alpha (PPARα) Signaling to Significantly Reduce Liver Fat Content

Guilherme S. Mazzini et al.

Summary: The study showed that RYGB led to greater liver fat loss than a low-calorie diet, which was associated with increased fasting BA levels and increased expression of modulators of liver fat oxidation, FXR, and PPAR alpha. However, intact PPAR alpha signaling was necessary for resolution of NAFLD after RYGB.

JOURNAL OF GASTROINTESTINAL SURGERY (2021)

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News Item Gastroenterology & Hepatology

Research in brief

Holly Baker

LANCET GASTROENTEROLOGY & HEPATOLOGY (2021)

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Review Cell Biology

The Role and Mechanism of Oxidative Stress and Nuclear Receptors in the Development of NAFLD

Ting Hong et al.

Summary: The overproduction of ROS and oxidative stress play crucial roles in the pathogenesis of acute and chronic liver diseases. NAFLD is characterized as a redox-centered disease, and dysregulation of nuclear receptors (NRs) may be key in regulating this process. Targeting NRs could be a promising strategy for improving oxidation damage and treating NAFLD.

OXIDATIVE MEDICINE AND CELLULAR LONGEVITY (2021)

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Review Pharmacology & Pharmacy

The pathophysiological function of non-gastrointestinal farnesoid X receptor

Nana Yan et al.

Summary: FXR influences bile acid homeostasis and the progression of various diseases. Studies show that FXR signaling improves experimentally-induced metabolic and immune diseases, but the downstream pathways regulated by FXR are diverse and tissue/cell-specific, leading to paradoxical effects in some disease models. Rescuing FXR expression could enhance the therapeutic effect of FXR agonists in compromised signaling pathways by diseases.

PHARMACOLOGY & THERAPEUTICS (2021)

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Review Gastroenterology & Hepatology

The role of farnesoid X receptor in metabolic diseases, and gastrointestinal and liver cancer

Lulu Sun et al.

Summary: FXR plays a crucial role in metabolic diseases and gastrointestinal and liver cancers by regulating bile acid synthesis and enterohepatic circulation, influencing glucose and lipid homeostasis. Targeting FXR signaling and bile acid metabolites may provide potential strategies for prevention and treatment of gastrointestinal and liver cancers.

NATURE REVIEWS GASTROENTEROLOGY & HEPATOLOGY (2021)

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Article Gastroenterology & Hepatology

Hepatic Small Ubiquitin-Related Modifier (SUMO)-Specific Protease 2 Controls Systemic Metabolism Through SUMOylation-Dependent Regulation of Liver-Adipose Tissue Crosstalk

Yang Liu et al.

Summary: The liver-specific knockout of SENP2 in mice showed resistance to high-fat diet-induced hepatic steatosis and obesity, upregulation of genes involved in fatty acid oxidation, and downregulation of genes in lipogenesis. Additionally, ablation of hepatic SENP2 activated thermogenesis in adipose tissues, promoting energy homeostasis. FGF21 was identified as a key factor in maintaining metabolic balance in SENP2 knockout mice.

HEPATOLOGY (2021)

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Review Cell Biology

Bile Acid Receptors and the Gut-Liver Axis in Nonalcoholic Fatty Liver Disease

Rui Xue et al.

Summary: The prevalence of NAFLD has increased due to obesity epidemic, with disease progression linked to inflammation, insulin resistance, and dysbiosis. Efforts to understand the mechanisms remain incomplete, but targeting BA-mediated signaling pathways offers potential for therapeutic development.

CELLS (2021)

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Article Gastroenterology & Hepatology

Elafibranor and liraglutide improve differentially liver health and metabolism in a mouse model of non-alcoholic steatohepatitis

Nikolaos Perakakis et al.

Summary: This study demonstrated that elafibranor and liraglutide can improve metabolic health and liver status in patients with non-alcoholic fatty liver disease (NAFLD) through different pathways, indicating important differences in mechanisms of action and suggesting potential as combination therapies in the future.

LIVER INTERNATIONAL (2021)

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Article Endocrinology & Metabolism

Elafibranor improves diet-induced nonalcoholic steatohepatitis associated with heart failure with preserved ejection fraction in Golden Syrian hamsters

Francois Briand et al.

Summary: The nutritional hamster model developed in this study successfully replicates the human phenotype of NASH and HFpEF, providing a valuable tool for validating novel drug candidates for the treatment of NASH and associated HFpEF.

METABOLISM-CLINICAL AND EXPERIMENTAL (2021)

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Review Gastroenterology & Hepatology

Therapeutic aspects of bile acid signalling in the gut-liver axis

Benedikt Simbrunner et al.

Summary: Bile acids play a crucial role in maintaining bile acid homeostasis and regulating the development of liver diseases through the gut-liver axis. The nuclear bile acid farnesoid X receptor (FXR) has emerged as a key therapeutic target in bile acid signalling pathways. Experimental evidence suggests that bile acid signalling can improve the intestinal barrier and protect against bacterial translocation in cirrhosis, showing efficacy in cholestatic and metabolic liver diseases. However, further research is needed to demonstrate similar effects in advanced liver disease, particularly in patients with decompensated cirrhosis.

ALIMENTARY PHARMACOLOGY & THERAPEUTICS (2021)

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Article Gastroenterology & Hepatology

Randomised clinical trial: Pemafibrate, a novel selective peroxisome proliferator-activated receptor alpha modulator (SPPARM alpha), versus placebo in patients with non-alcoholic fatty liver disease

Atsushi Nakajima et al.

Summary: In patients with high-risk non-alcoholic fatty liver disease, Pemafibrate did not reduce liver fat content but significantly decreased liver stiffness based on magnetic resonance elastography. There was also a significant reduction in ALT and LDL-C levels during the treatment period.

ALIMENTARY PHARMACOLOGY & THERAPEUTICS (2021)

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Article Cell Biology

FXR activation protects against NAFLD via bile-acid-dependent reductions in lipid absorption

Bethan L. Clifford et al.

Summary: FXR agonists are used to treat NAFLD by controlling hepatic lipid absorption and fatty acid synthesis, specifically reducing levels of MUFA and PUFA in the liver. This reduction is mediated by repression of specific genes and is independent of other regulatory factors like SHP and SREBP1c. Additionally, tissue-specific FXR KO mice studies show that hepatic FXR controls lipogenic genes while intestinal FXR controls lipid absorption.

CELL METABOLISM (2021)

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Review Biochemistry & Molecular Biology

Mechanisms Mediating the Regulation of Peroxisomal Fatty Acid Beta-Oxidation by PPARα

Mounia Tahri-Joutey et al.

Summary: This article discusses the shared ability of mitochondria and peroxisomes in degrading fatty acid chains, the hepatomegaly effect caused by clofibrate, the identification of peroxisome proliferators and their impact on the peroxisomal fatty acid beta-oxidation pathway, and the modulation of PPAR alpha function by dietary micronutrients.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2021)

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Article Oncology

Disordered farnesoid X receptor signaling is associated with liver carcinogenesis in Abcb11-deficient mice

Liping Wang et al.

Summary: ABCB11 is downregulated in liver tumors, and Abcb11-deficient mice develop HCC and ICC with worsening cholestasis and liver fibrosis. FXR agonist can reduce liver injury and tumor incidence in Abcb11-deficient mice.

JOURNAL OF PATHOLOGY (2021)

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Article Biochemistry & Molecular Biology

Efruxifermin in non-alcoholic steatohepatitis: a randomized, double-blind, placebo-controlled, phase 2a trial

Stephen A. Harrison et al.

Summary: The study demonstrated the efficacy of efruxifermin in treating NASH by significantly reducing HFF levels in patients, with an acceptable safety profile.

NATURE MEDICINE (2021)

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Review Cardiac & Cardiovascular Systems

PPAR control of metabolism and cardiovascular functions

David Montaigne et al.

Summary: Novel PPAR agonists offer new opportunities for managing metabolic and cardiovascular diseases by regulating gene expression, lipid metabolism, insulin sensitivity, glucose metabolism, and cardiovascular health. Activation of PPARs by specific ligands can have antiatherogenic, anti-inflammatory, and metabolic benefits, making them important therapeutic targets in the treatment of various diseases.

NATURE REVIEWS CARDIOLOGY (2021)

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Review Gastroenterology & Hepatology

Role of FXR in Bile Acid and Metabolic Homeostasis in NASH: Pathogenetic Concepts and Therapeutic Opportunities

Richard Radun et al.

Summary: NAFLD and NASH are common liver diseases, with their pathogenesis potentially involving disturbance in bile acid homeostasis and the FXR signaling pathway. FXR serves as a key regulator of bile acid metabolism, as well as having roles in metabolic regulation and immune modulation, making it a promising therapeutic target for NAFLD/NASH.

SEMINARS IN LIVER DISEASE (2021)

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Article Gastroenterology & Hepatology

Saroglitazar, a PPAR-α/γ Agonist, for Treatment of NAFLD: A Randomized Controlled Double-Blind Phase 2 Trial

Samer Gawrieh et al.

Summary: Saroglitazar showed significant efficacy in patients with NAFLD/NASH, improving ALT, liver fat content and insulin resistance. The 4mg dose of Saroglitazar also demonstrated significant improvements in lipid metabolism and lipoprotein particle composition. Overall, Saroglitazar was well-tolerated with a slight weight gain observed in patients.

HEPATOLOGY (2021)

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Review Biochemistry & Molecular Biology

Farnesoid X receptor (FXR): Structures and ligands

Longying Jiang et al.

Summary: FXR is a crucial bile acid activated nuclear receptor that regulates key genes involved in bile acid metabolism. With the approval of OCA as the first small molecule targeting FXR, many other FXR-targeting small molecules are currently being evaluated in clinical trials.

COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL (2021)

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Review Gastroenterology & Hepatology

Effect of different bile acids on the intestine through enterohepatic circulation based on FXR

Junwei Xiang et al.

Summary: FXR, a nuclear receptor for bile acids, plays a key role in regulating metabolic pathways and improving various diseases. Bile acids link the intestine with the liver through the enterohepatic circulation, with different types of bile acids having diverse effects on the intestines, providing a foundation for new treatment methods.

GUT MICROBES (2021)

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Article Endocrinology & Metabolism

Metabolic Messengers: FGF21

Kyle H. Flippo et al.

Summary: FGF21, a non-canonical fibroblast growth factor, acts as an endocrine hormone signaling to various targets in the body. Initially recognized for its potential in correcting metabolic dysfunction and reducing body weight associated with diabetes and obesity, new functions of FGF21 signaling have emerged, demonstrating its ability to regulate macronutrient preference and energy balance.

NATURE METABOLISM (2021)

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Review Endocrinology & Metabolism

Immunoregulatory Functions of Nuclear Receptors: Mechanisms and Therapeutic Implications

Linjie Zhao et al.

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Role of farnesoid X receptor in hepatic steatosis in nonalcoholic fatty liver disease

Yingfei Xi et al.

BIOMEDICINE & PHARMACOTHERAPY (2020)

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Tropifexor, a highly potent FXR agonist, produces robust and dose-dependent reductions in hepatic fat and serum alanine aminotransferase in patients with fibrotic NASH after 12 weeks of therapy: FLIGHT-FXR Part C interim results

K. J. Lucas et al.

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Cilofexor, a NonsteroidalFXRAgonist, in Patients With Noncirrhotic NASH: A Phase 2 Randomized Controlled Trial

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PPARs as Metabolic Regulators in the Liver: Lessons from Liver-Specific PPAR-Null Mice

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Volixibat in adults with non-alcoholic steatohepatitis: 24-week interim analysis from a randomized, phase II study

Philip N. Newsome et al.

JOURNAL OF HEPATOLOGY (2020)

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Bile acid-based therapies for non-alcoholic steatohepatitis and alcoholic liver disease

Tiangang Li et al.

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Review Cell Biology

Peroxisome Proliferator-Activated Receptors and Their Novel Ligands as Candidates for the Treatment of Non-Alcoholic Fatty Liver Disease

Anne Fougerat et al.

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Focus shifts to antibody cocktails for COVID-19 cytokine storm

Charlotte Harrison

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Novel insights into the organic solute transporter alpha/beta, OSTα/β: From the bench to the bedside

James J. Beaudoin et al.

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Article Gastroenterology & Hepatology

Nidufexor, a non-bile acid FXR agonist, decreases ALT and hepatic fat fraction in patients with NASH after 12 weeks dosing

Richard Aspinall et al.

JOURNAL OF HEPATOLOGY (2020)

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Activation of PPARα decreases bile acids in livers of female mice while maintaining bile flow and biliary bile acid excretion

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Clofibrate Decreases Bile Acids in Livers of Male Mice by Increasing Biliary Bile Acid Excretion in a PPARα-Dependent Manner

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miR-21 ablation and obeticholic acid ameliorate nonalcoholic steatohepatitis in mice

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Effects of K-877, a novel selective PPARα modulator (SPPARMα), in dyslipidaemic patients: A randomized, double blind, active- and placebo-controlled, phase 2 trial

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Elafibranor, an Agonist of the Peroxisome Proliferator-Activated Receptor-α and -δ, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening

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An Intestinal Microbiota-Farnesoid X Receptor Axis Modulates Metabolic Disease

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Liver PPARα is crucial for whole-body fatty acid homeostasis and is protective against NAFLD

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PPARα gene expression correlates with severity and histological treatment response in patients with non-alcoholic steatohepatitis

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Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance

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Fibroblast Growth Factor 21 Limits Lipotoxicity by Promoting Hepatic Fatty Acid Activation in Mice on Methionine and Choline-Deficient Diets

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Hepatic Carboxylesterase 1 Is Essential for Both Normal and Farnesoid X Receptor-Controlled Lipid Homeostasis

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PPARα-UGT axis activation represses intestinal FXR-FGF15 feedback signalling and exacerbates experimental colitis

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Amelioration by chicory seed extract of diabetes- and oleic acid-induced non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) via modulation of PPAR alpha and SREBP-1

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Mechanism of tissue-specific farnesoid X receptor in suppressing the expression of genes in bile-acid synthesis in mice

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Activation of the Farnesoid X Receptor Induces Hepatic Expression and Secretion of Fibroblast Growth Factor 21

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Mouse organic solute transporter alpha deficiency alters FGF15 expression and bile acid metabolism

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Metabolomics reveals an essential role for peroxisome proliferator-activated receptor α in bile acid homeostasis

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Genome-Wide Profiling of Liver X Receptor, Retinoid X Receptor, and Peroxisome Proliferator-Activated Receptor α in Mouse Liver Reveals Extensive Sharing of Binding Sites

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ChREBP Mediates Glucose Repression of Peroxisome Proliferator-activated Receptor α Expression in Pancreatic β-Cells

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Human SREBP1c Expression in Liver Is Directly Regulated by Peroxisome Proliferator-activated Receptor α (PPARα)

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Effects of nuclear receptor FXR on the regulation of liver lipid metabolism in patients with non-alcoholic fatty liver disease

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Fibroblast Growth Factor-19, a Novel Factor That Inhibits Hepatic Fatty Acid Synthesis

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A pilot trial of fenofibrate for the treatment of non-alcoholic fatty liver disease

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Regulation of transporter expression in mouse liver, kidney, and intestine during extrahepatic cholestasis

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Farnesoid X receptor is essential for normal glucose homeostasis

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Role of nuclear receptors and hepatocyte-enriched transcription factors for Ntcp repression in biliary obstruction in mouse liver

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The orphan nuclear receptor SHP regulates PGC-1α expression and energy production in brown adipocytes

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Bile acid-induced negative feedback regulation of the human lleal bile acid transporter

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Bile acids induce the expression of the human peroxisome proliferator-activated receptor α gene via activation of the farnesoid X receptor

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Loss of nuclear receptor SHP impairs but does not eliminate negative feedback regulation of bile acid synthesis

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Farnesoid X receptor and bile salts are involved in transcriptional regulation of the gene encoding the human bile salt export pump

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Antagonism of the actions of peroxisome proliferator-activated receptor-α by bile acids

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The orphan nuclear receptor, shp, mediates bile acid-induced inhibition of the rat bile acid transporter, ntcp

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Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis

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A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis

B Goodwin et al.

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Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors

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