Emerging functions of the nuclear receptor LRH-1 in liver physiology and pathology

Sun, Yu; Demagny, Hadrien

doi:10.1016/j.bbadis.2021.166145

Cited by 28 publications

(21 citation statements)

References 120 publications

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“…This may apply in selected patients without a history of chronic hepatitis such as chronic hepatitis B or C, as we have excluded them. However, this association should be confirmed by further studies revealing the detailed mechanism [ 34 , 35 ].…”

Section: Discussionmentioning

confidence: 97%

Elevated alpha-fetoprotein in asymptomatic adults: Clinical features, outcome, and association with body composition

et al. 2022

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Background and aim Apparently healthy individuals with elevated serum alpha-fetoprotein (AFP) levels (>7 ng/mL) for unknown causes visit clinics. We investigated their clinical characteristics, outcomes, and relationship with body fat deposition and muscle mass. Methods The case group included asymptomatic 137 individuals with “elevated AFP level” (R772) diagnostic code from 2009 to 2018 in a tertiary hospital. The control group enrolled 274 age- and sex-matched patients with <5 cm hepatic hemangiomas. Hepatic, visceral, and psoas muscle adiposity and psoas muscle index (PMI) were measured in the subgroups of 45 cases and 90 controls with pre-contrast computed tomography (CT) images. Results The case group (mean age 47.5 years, male 35.8%) showed higher AFP levels (10.3 vs 2.5 ng/mL, p<0.001) and total bilirubin (0.8 vs 0.7 mg/dL, p<0.001), but a lower body mass index (22.2 vs 23.3 kg/m2, p = 0.011) and alanine aminotransferase levels (17.0 vs 19.0 IU/L, p = 0.047) than the controls. During 13 months of median follow-up, there was no cancer or liver disease development. The AFP levels were stable. In the subgroups with CT images, cases showed a lower proportion of hepatic steatosis (4.4% vs 18.9%, p = 0.023), higher psoas muscle attenuation (48.2 vs 43.8 Hounsfield units, p<0.001) and higher PMI (5.7 vs 4.2 cm2/m2, p<0.001) than the controls. Conclusion Elevated AFP levels in asymptomatic individuals may play a role in expressing a protective phenotype against hepatic steatosis, myosteatosis, and sarcopenia. AFP levels in patients with elevated AFP were stable during follow-up without liver injury or cancer development. Interaction between AFP expression and steatosis warrants further study.

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Section: Discussionmentioning

confidence: 97%

Elevated alpha-fetoprotein in asymptomatic adults: Clinical features, outcome, and association with body composition

et al. 2022

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“…LRH-1 agonist BL001 impedes β cell apoptosis in T2DM while it favors insulin secretion [ 266 ]. Notably, in the livers of LRH-1-knockout mice, the NADPH/NADP + and GSH/GSSG ratios are decreased, supporting the role of LRH-1 in facilitating NADPH generation [ 269 , 270 ]. In addition, evidence has shown that ROS production induced by a high concentration of palmitate in hepatocytes is reduced after LRH-1 agonist RJW101 intervention [ 271 ].…”

Section: Transcriptional Regulation Of Lipid Metabolism By Nrs In Nafldmentioning

confidence: 96%

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

Hong

Chen

et al. 2021

Oxidative Medicine and Cellular Longevity

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The overproduction of reactive oxygen species (ROS) and consequent oxidative stress contribute to the pathogenesis of acute and chronic liver diseases. It is now acknowledged that nonalcoholic fatty liver disease (NAFLD) is characterized as a redox-centered disease due to the role of ROS in hepatic metabolism. However, the underlying mechanisms accounting for these alternations are not completely understood. Several nuclear receptors (NRs) are dysregulated in NAFLD, and have a direct influence on the expression of a set of genes relating to the progress of hepatic lipid homeostasis and ROS generation. Meanwhile, the NRs act as redox sensors in response to metabolic stress. Therefore, targeting NRs may represent a promising strategy for improving oxidation damage and treating NAFLD. This review summarizes the link between impaired lipid metabolism and oxidative stress and highlights some NRs involved in regulating oxidant/antioxidant turnover in the context of NAFLD, shedding light on potential therapies based on NR-mediated modulation of ROS generation and lipid accumulation.

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“…Similar to other nuclear receptors, liver receptor homolog 1 (LRH-1) is a NR identified in the liver that exerts diverse metabolic functions including bile acid, lipid and glucose homeostasis [ 201 ]. Emerging evidence suggests a role for LRH-1 in NAFLD and NASH.…”

Section: Nuclear Receptor (Nrs) In Nafld/nash: Linking Metabolism And...mentioning

confidence: 99%

“…The LRH-1 K289R mutation activated OSBPL3, thereby enhancing the activation of SREBP-1, resulting in de novo lipogenesis. In addition, in NAFLD mouse models and patients, the aggregation of OSBPL3-related inflammation and fibrogenesis indicates that the LRH-1-OSBPL3 signal may trigger the pathogenesis of NASH [ 201 , 203 , 204 ]. Furthermore, RNA-seq data from NAFLD or NASH patients showed that LRH-1 was significantly downregulated [ 205 ].…”

Section: Nuclear Receptor (Nrs) In Nafld/nash: Linking Metabolism And...mentioning

confidence: 99%

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

Puengel

Liu

Guillot

et al. 2022

IJMS

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Nonalcoholic fatty liver disease (NAFLD) and its progressive form nonalcoholic steatohepatitis (NASH) comprise a spectrum of chronic liver diseases in the global population that can lead to end-stage liver disease and hepatocellular carcinoma (HCC). NAFLD is closely linked to the metabolic syndrome, and comorbidities such as type 2 diabetes, obesity and insulin resistance aggravate liver disease, while NAFLD promotes cardiovascular risk in affected patients. The pathomechanisms of NAFLD are multifaceted, combining hepatic factors including lipotoxicity, mechanisms of cell death and liver inflammation with extrahepatic factors including metabolic disturbance and dysbiosis. Nuclear receptors (NRs) are a family of ligand-controlled transcription factors that regulate glucose, fat and cholesterol homeostasis and modulate innate immune cell functions, including liver macrophages. In parallel with metabolic derangement in NAFLD, altered NR signaling is frequently observed and might be involved in the pathogenesis. Therapeutically, clinical data indicate that single drug targets thus far have been insufficient for reaching patient-relevant endpoints. Therefore, combinatorial treatment strategies with multiple drug targets or drugs with multiple mechanisms of actions could possibly bring advantages, by providing a more holistic therapeutic approach. In this context, peroxisome proliferator-activated receptors (PPARs) and other NRs are of great interest as they are involved in wide-ranging and multi-organ activities associated with NASH progression or regression. In this review, we summarize recent advances in understanding the pathogenesis of NAFLD, focusing on mechanisms of cell death, immunometabolism and the role of NRs. We outline novel therapeutic strategies and discuss remaining challenges.

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Emerging functions of the nuclear receptor LRH-1 in liver physiology and pathology

Cited by 28 publications

References 120 publications

Elevated alpha-fetoprotein in asymptomatic adults: Clinical features, outcome, and association with body composition

Elevated alpha-fetoprotein in asymptomatic adults: Clinical features, outcome, and association with body composition

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

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

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