Glycine-based treatment ameliorates NAFLD by modulating fatty acid oxidation, glutathione synthesis, and the gut microbiome

Published on Dec 2, 2020in Science Translational Medicine16.304
· DOI :10.1126/SCITRANSLMED.AAZ2841
Oren Rom16
Estimated H-index: 16
(UM: University of Michigan),
Yuhao Liu4
Estimated H-index: 4
(UM: University of Michigan)
+ 30 AuthorsY. Eugene Chen59
Estimated H-index: 59
(UM: University of Michigan)
Sources
Abstract
Nonalcoholic fatty liver disease (NAFLD) including nonalcoholic steatohepatitis (NASH) has reached epidemic proportions with no pharmacological therapy approved. Lower circulating glycine is consistently reported in patients with NAFLD, but the causes for reduced glycine, its role as a causative factor, and its therapeutic potential remain unclear. We performed transcriptomics in livers from humans and mice with NAFLD and found suppression of glycine biosynthetic genes, primarily alanine-glyoxylate aminotransferase 1 (AGXT1). Genetic (Agxt1−/− mice) and dietary approaches to limit glycine availability resulted in exacerbated diet-induced hyperlipidemia and steatohepatitis, with suppressed mitochondrial/peroxisomal fatty acid β-oxidation (FAO) and enhanced inflammation as the underlying pathways. We explored glycine-based compounds with dual lipid/glucose-lowering properties as potential therapies for NAFLD and identified a tripeptide (Gly-Gly-L-Leu, DT-109) that improved body composition and lowered circulating glucose, lipids, transaminases, proinflammatory cytokines, and steatohepatitis in mice with established NASH induced by a high-fat, cholesterol, and fructose diet. We applied metagenomics, transcriptomics, and metabolomics to explore the underlying mechanisms. The bacterial genus Clostridium sensu stricto was markedly increased in mice with NASH and decreased after DT-109 treatment. DT-109 induced hepatic FAO pathways, lowered lipotoxicity, and stimulated de novo glutathione synthesis. In turn, inflammatory infiltration and hepatic fibrosis were attenuated via suppression of NF-κB target genes and TGFβ/SMAD signaling. Unlike its effects on the gut microbiome, DT-109 stimulated FAO and glutathione synthesis independent of NASH. In conclusion, impaired glycine metabolism may play a causative role in NAFLD. Glycine-based treatment attenuates experimental NAFLD by stimulating hepatic FAO and glutathione synthesis, thus warranting clinical evaluation.
References76
Newest
#1Sonsoles Salto-Alejandre (University of Seville)H-Index: 3
#2Judith Berastegui-Cabrera (University of Seville)H-Index: 4
Last. Rosario AmayaH-Index: 1
view all 15 authors...
The aim was to assess the ability of nasopharyngeal SARS-CoV-2 viral load at first patient’s hospital evaluation to predict unfavorable outcomes. We conducted a prospective cohort study including 321 adult patients with confirmed COVID-19 through RT-PCR in nasopharyngeal swabs. Quantitative Synthetic SARS-CoV-2 RNA cycle threshold values were used to calculate the viral load in log10 copies/mL. Disease severity at the end of follow up was categorized into mild, moderate, and severe. Primary endp...
1 CitationsSource
#1Laura B. L. Wittemans (University of Cambridge)H-Index: 6
#2Luca A. Lotta (University of Cambridge)H-Index: 22
Last. Claudia Langenberg (University of Cambridge)H-Index: 122
view all 23 authors...
Circulating levels of glycine have previously been associated with lower incidence of coronary heart disease (CHD) and type 2 diabetes (T2D) but it remains uncertain if glycine plays an aetiological role. We present a meta-analysis of genome-wide association studies for glycine in 80,003 participants and investigate the causality and potential mechanisms of the association between glycine and cardio-metabolic diseases using genetic approaches. We identify 27 genetic loci, of which 22 have not pr...
35 CitationsSource
#1Oren RomH-Index: 16
#2Guan XuH-Index: 18
Last. Luis VillacortaH-Index: 24
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Abstract Background Nonalcoholic fatty liver disease (NAFLD) and resulting nonalcoholic steatohepatitis (NASH) are reaching global epidemic proportions. Lack of non-invasive diagnostic tools and effective therapies constitute two of the major hurdles for a bona fide treatment and a reversal of NASH progression and/or regression of the disease. Nitro-oleic acid (OA-NO2) has been proven effective in multiple experimental models of inflammation and fibrosis. Thus, the potential benefit of in vivo a...
21 CitationsSource
#1Ramy Younes (UNITO: University of Turin)H-Index: 10
#2Elisabetta Bugianesi (UNITO: University of Turin)H-Index: 79
In 2018, there have been substantial advances in our understanding of the risk factors for advanced liver disease in nonalcoholic fatty liver disease, including genetic variants and the gut microbiota. Promising results have also arisen from drugs targeting metabolic pathways involved in the progression of liver damage.
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#2Luis Villacorta (UM: University of Michigan)H-Index: 24
Last. Michael Aviram (Technion – Israel Institute of Technology)H-Index: 107
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#1Scott L. Friedman (ISMMS: Icahn School of Medicine at Mount Sinai)H-Index: 142
#1Scott L. Friedman (ISMMS: Icahn School of Medicine at Mount Sinai)H-Index: 3
Last. Arun J. Sanyal (VCU: Virginia Commonwealth University)H-Index: 121
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#1Lesley Hoyles (Imperial College London)H-Index: 26
#2José Manuel Fernández-Real (ISCIII: Carlos III Health Institute)H-Index: 91
Last. Marc-Emmanuel Dumas (Imperial College London)H-Index: 41
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#1Melania Gaggini (National Research Council)H-Index: 18
#2Fabrizia Carli (National Research Council)H-Index: 6
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Plasma concentrations of amino acids (AAs), in particular, branched chain AAs (BCAAs), are often found increased in nonalcoholic fatty liver disease (NAFLD); however, if this is due to increased muscular protein catabolism, obesity, and/or increased insulin resistance (IR) or impaired tissue metabolism is unknown. Thus, we evaluated a) if subjects with NAFLD without obesity (NAFLD-NO) compared to those with obesity (NAFLD-Ob) display altered plasma AAs compared to controls (CTs); and b) if AA co...
116 CitationsSource
#1Xianghui Li (PKU: Peking University)H-Index: 3
#2Liang Sun (PKU: Peking University)H-Index: 60
Last. Jun Dong (PKU: Peking University)H-Index: 4
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Several studies have identified a negative association between serum glycine (Gly) levels and metabolic syndrome (MetS). However, this association has not been fully established in the elderly. A total of 472 Chinese individuals (272 males and 200 females, 70.1 ± 6.6 years old) participated in a population-based, cross-sectional survey in Beijing Hospital. The MetS and its components were defined based on the 2006 International Diabetes Federation (IDF) standard for Asians. Serum Gly concentrati...
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Fatty liver disease (FLD) increases the risk of diabetes, cardiovascular disease, and steatohepatitis, which leads to fibrosis, cirrhosis, and hepatocellular carcinoma. Thus, the early detection of FLD is necessary. We aimed to find a quantitative and feasible model for discriminating the FLD, based on plasma free amino acid (PFAA) profiles. We constructed models of the relationship between PFAA levels in 2,000 generally healthy Japanese subjects and the diagnosis of FLD by abdominal ultrasound ...
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Non-alcoholic fatty liver disease (NAFLD), which often co-occurs with obesity and type 2 diabetes, is the most common cause of chronic liver disease worldwide. null A subset of patients with NAFLD progress to the severe form known as non-alcoholic steatohepatitis (NASH), which increases the risk of developing hepatic fibrosis, cirrhosis, and hepatocellular carcinoma. null The molecular underpinnings of the progression from NAFLD to NASH in patients is poorly understood. null Active enhancer land...
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