Genome-wide association and Mendelian randomization study of fibroblast growth factor 21 reveals causal associations with hyperlipidemia and possibly NASH

Larsson, Susanna C.; Michaëlsson, Karl; Mola-Caminal, Marina; Höijer, Jonas; Mantzoros, Christos S.

doi:10.1016/j.metabol.2022.155329

Cited by 24 publications

(11 citation statements)

References 54 publications

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“… Similar circulating FGF-21 between different hepatic fibrosis stages. Larsson (2022) 67 Cross-sectional Genome-wide association study in adults (6259); replication in women (4483) SNP rs2548957 of FGF-21 gene was associated with higher circulating FGF-21. SNP rs2548957 of FGF-21 gene was associated with lower GGT, but not HFC or the presence of NAFLD.…”

Section: Clinical Studiesmentioning

confidence: 99%

“… 66 In a more recent genome-wide association study (GWAS) with large sample size, the rs2548957 of FGF-21 gene was shown to be associated with circulating FGF-21 concentrations, as well as with lower gamma-glutamyltransferase (GGT), but not HFC or NAFLD. 67 Of course, more studies are needed to validate these findings and investigate whether they are of clinical implication.…”

Section: Clinical Studiesmentioning

confidence: 99%

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Fibroblast Growth Factor-21 as a Potential Therapeutic Target of Nonalcoholic Fatty Liver Disease

Raptis¹,

Mantzoros²,

Polyzos³

2023

TCRM

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Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent disease without any approved treatment to-date despite intensive research efforts by researchers and pharmaceutical industry. Fibroblast growth factor (FGF)-21 has been gaining increasing attention as a possible contributing factor and thus therapeutic target for obesity-related metabolic disorders, including NAFLD, mainly due to its effects on lipid and carbohydrate metabolism. Most animal and human observational studies have shown higher FGF-21 concentrations in NAFLD than non-NAFLD, implying that FGF-21 may be increased to counteract hepatic steatosis and inflammation. However, although Mendelian Randomization studies have revealed that variations of FGF-21 levels within the physiological range may have effects in hyperlipidemia and possibly nonalcoholic steatohepatitis, they also indicate that FGF-21, in physiological concentrations, may fail to reverse NAFLD and may not be able to control obesity and other diseases, indicating a state of FGF-21 resistance or insensitivity that could not respond to administration of FGF-21 in supraphysiological concentrations. Interventional studies with FGF-21 analogs (eg, pegbelfermin, efruxifermin, BOS-580) in humans have provided some favorable results in Phase 1 and Phase 2 studies. However, the definite effect of FGF-21 on NAFLD may be clarified after the completion of the ongoing clinical trials with paired liver biopsies and histological endpoints. The aim of this review is to critically summarize experimental and clinical data of FGF-21 in NAFLD, in an attempt to highlight existing knowledge and areas of uncertainty, and subsequently, to focus on the potential therapeutic effects of FGF-21 and its analogs in NAFLD.

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Section: Clinical Studiesmentioning

confidence: 99%

Section: Clinical Studiesmentioning

confidence: 99%

Fibroblast Growth Factor-21 as a Potential Therapeutic Target of Nonalcoholic Fatty Liver Disease

Raptis¹,

Mantzoros²,

Polyzos³

2023

TCRM

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“…However, the relationships between the other two proteins and diabetes remain controversial, especially for FGF21 [ 58 ]. While increased circulating FGF-21 levels was linked to elevated risk of diabetes [ 59 ], null results were reported in Mendelian Randomization investigations [ 60 ]. FGF-21 was report to enhance skeletal muscle glucose uptake [ 61 ] and protect lipid disruption and nonalcoholic steatohepatitis [ 60 , 62 ], even in a clinical trial [ 63 ].…”

Section: Discussionmentioning

confidence: 99%

Metabolic and inflammatory perturbation of diabetes associated gut dysbiosis in people living with and without HIV infection

Luo,

Peters,

Moon

et al. 2024

Genome Med

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Background Gut dysbiosis has been linked with both HIV infection and diabetes, but its interplay with metabolic and inflammatory responses in diabetes, particularly in the context of HIV infection, remains unclear. Methods We first conducted a cross-sectional association analysis to characterize the gut microbial, circulating metabolite, and immune/inflammatory protein features associated with diabetes in up to 493 women (~ 146 with prevalent diabetes with 69.9% HIV +) of the Women’s Interagency HIV Study. Prospective analyses were then conducted to determine associations of identified metabolites with incident diabetes over 12 years of follow-up in 694 participants (391 women from WIHS and 303 men from the Multicenter AIDS Cohort Study; 166 incident cases were recorded) with and without HIV infection. Mediation analyses were conducted to explore whether gut bacteria–diabetes associations are explained by altered metabolites and proteins. Results Seven gut bacterial genera were identified to be associated with diabetes (FDR-q < 0.1), with positive associations for Shigella, Escherichia, Megasphaera, and Lactobacillus, and inverse associations for Adlercreutzia, Ruminococcus, and Intestinibacter. Importantly, the associations of most species, especially Adlercreutzia and Ruminococcus, were largely independent of antidiabetic medications use. Meanwhile, 18 proteins and 76 metabolites, including 3 microbially derived metabolites (trimethylamine N-oxide, phenylacetylglutamine (PAGln), imidazolepropionic acid (IMP)), 50 lipids (e.g., diradylglycerols (DGs) and triradylglycerols (TGs)) and 23 non-lipid metabolites, were associated with diabetes (FDR-q < 0.1), with the majority showing positive associations and more than half of them (59/76) associated with incident diabetes. In mediation analyses, several proteins, especially interleukin-18 receptor 1 and osteoprotegerin, IMP and PAGln partially mediate the observed bacterial genera–diabetes associations, particularly for those of Adlercreutzia and Escherichia. Many diabetes-associated metabolites and proteins were altered in HIV, but no effect modification on their associations with diabetes was observed by HIV. Conclusion Among individuals with and without HIV, multiple gut bacterial genera, blood metabolites, and proinflammatory proteins were associated with diabetes. The observed mediated effects by metabolites and proteins in genera–diabetes associations highlighted the potential involvement of inflammatory and metabolic perturbations in the link between gut dysbiosis and diabetes in the context of HIV infection.

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“…102,103 Pegbelfermin, a pegylated FGF21 analog, administered for 16 weeks to patients with NASH decreases hepatic steatosis evaluated by MRI. 104 Recently, a strong causal effect of FGF21 on improved lipid profile and liver function biomarkers including fibrosis has reported by Larsson et al 105 Markers of hepatocyte apoptosis. Cytokeratin 18 (CK18), the major intermediate filament protein within hepatocytes, is cleaved during initiation of cell death leading to extracellular release.…”

Section: Albuminmentioning

confidence: 97%

Impact of obesity on liver function tests: is nonalcoholic fatty liver disease the only player? A review article

El-Eshmawy

2023

Porto Biomedical Journal

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Objectives: Obesity and nonalcoholic fatty liver disease (NAFLD) are common worldwide health problems with a strong relationship in between. NAFLD is currently the most common cause of abnormal liver function tests (LFT) because of obesity pandemic. The question is NAFLD the only player of abnormal LFT in obesity? Methodology: This article reviews the most important topics regarding the derangements of LFT in obesity through a PubMed search strategy for all English-language literature. Results: The reported abnormal LFT in obesity were increased serum levels of transaminases (alanine aminotransaminase, aspartate aminotransaminase), gamma glutamyl transferase, and alkaline phosphatase and decreased serum levels of bilirubin and albumin. Besides novel potential hepatic markers of NAFLD/NASH such as triglycerides/high-density lipoprotein cholesterol ratio, sex hormone–binding globulin, fibroblast growth factor 21, and markers of hepatocyte apoptosis i.e. cytokeratin 18 and microribonucleic acids (miRNAs). Beyond NAFLD, there are other underlying players for the abnormal LFT in obesity such as oxidative stress, inflammation, and insulin resistance. Conclusion: Derangements of LFT in obesity are attributed to NAFLD but also to obesity itself and its related oxidative stress, insulin resistance, and chronic inflammatory state. Abnormal LFT predict more than just liver disease.

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Genome-wide association and Mendelian randomization study of fibroblast growth factor 21 reveals causal associations with hyperlipidemia and possibly NASH

Cited by 24 publications

References 54 publications

Fibroblast Growth Factor-21 as a Potential Therapeutic Target of Nonalcoholic Fatty Liver Disease

Fibroblast Growth Factor-21 as a Potential Therapeutic Target of Nonalcoholic Fatty Liver Disease

Metabolic and inflammatory perturbation of diabetes associated gut dysbiosis in people living with and without HIV infection

Impact of obesity on liver function tests: is nonalcoholic fatty liver disease the only player? A review article

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