Targeting Hepatic Glutaminase 1 Ameliorates Non-Alcoholic Steatohepatitis by Restoring Disrupted Hepatic Very-Low Density Lipoproteins Triglyceride Assembly

Simón, Jorge; Núñez-García, Maitane; Fernández-Tussy, Pablo; Barbier-Torres, Lucía; Fernández‐Ramos, David; Gómez‐Santos, Beatriz; Buqué, Xabier; Lopitz‐Otsoa, Fernando; Zubiete-Franco, Imanol; Juan, Virginia Gutiérrez‐de; Cabrera, Diana; Alonso, Cristina; Iruzubieta, Paula; Liempd, Sebastiaan van; Castro, Azucena; Varela‐Rey, Marta; Falcón‐Pérez, Juan Manuel; Villa, Erica; Crespo, Javier; Lu, Shelly C.; Mato, José M.; Aspichueta, Patricia; Delgado, Teresa C.; Chantar, M.L.M.

doi:10.2139/ssrn.3219265

Cited by 2 publications

(6 citation statements)

References 54 publications

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“…Previous studies have reported a strong associations between NAFLD and the glutamine pathway and urea cycle 13,14 that are involved in intracellular fatty acid accumulation and fibrogenesis. L-glutamine is the most abundant free amino acid in the human body.…”

Section: Glutaminolysis and The Urea Cyclementioning

confidence: 98%

“…25,26 However, its role in the progression of liver diseases like NAFLD has not been described. Glutaminolysis, mainly GLS activity, has been associated with (a) the accumulation of intracellular lipids by hepatocytes, 13 (b) HSC activation and fibrosis progression, 14,27 and (c) metabolic reprogramming that is needed to fuel cancer cell growth. 28…”

Section: Glutaminolysis and The Urea Cyclementioning

confidence: 99%

“…There are several hypotheses about the nitrogen imbalance in NAFLD. Although further studies are needed for confirmation, they include (a) intestinal dysbiosis or microbiota changes; 21 (b) increased glutaminolysis, 13 (c) urea cycle dysfunction, 32 and (d) decrease of glutamine synthesize activity. 33…”

Section: Glutamine Metabolism and Nafldmentioning

confidence: 99%

“…Recently, Simon et al 13 showed that GLS was overexpressed in the livers of NASH patients and in mice in diet-induced NASH models, providing evidence that glutamine metabolism is a potential therapeutic target in NASH progression. It is well known that dysfunction of very-low-density lipoprotein (VLDL) synthesis and secretion occurs in NASH.…”

Section: Steatosis and The Glutamine-ammonia-urea Cycle Axismentioning

confidence: 99%

“…In addition, if Gls was silenced in mice fed a 0.1% MCDD and cholinedeficient high-fat diet (CD-HFD) then the fat content of the liver decreased because of the restoration of VLDL synthesis pathways and reduction of oxidative metabolism. 13…”

Section: Steatosis and The Glutamine-ammonia-urea Cycle Axismentioning

confidence: 99%

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Glutaminolysis-ammonia-urea Cycle Axis, Non-alcoholic Fatty Liver Disease Progression and Development of Novel Therapies

Rojas¹,

García-Lozano²,

Gil‐Gómez³

et al. 2022

J Clin Transl Hepatol

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The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing worldwide, reflecting the current epidemics of obesity, insulin resistance, type 2 diabetes mellitus, and metabolic syndrome. NAFLD is characterized by the accumulation of fat in the liver, and is known to be a cause of cirrhosis. Although many pathways have been proposed, the cause of NAFLD-linked fibrosis progression is still unclear, which posed challenges for the development of new therapies to prevent NASH-related cirrhosis and hepatocellular carcinoma. Cirrhosis is associated with activation of hepatic stellate cells (HSC) and accumulation of excess extracellular matrix proteins, and inhibiting the activation of HSCs would be expected to slow the progression of NAFLD-cirrhosis. Multiple molecular signals and pathways such as oxidative stress and glutaminolysis have been reported to promote HSC activation. Both mechanisms are plausible antifibrotic targets in NASH, as the activation of HSCs the proliferation of myofibroblasts depend on those processes. This review summarizes the role of the glutaminolysis-ammonia-urea cycle axis in the context of NAFLD progression, and shows how the axis could be a novel therapeutic target.

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Section: Glutaminolysis and The Urea Cyclementioning

confidence: 98%

Section: Glutaminolysis and The Urea Cyclementioning

confidence: 99%

Section: Glutamine Metabolism and Nafldmentioning

confidence: 99%

Section: Steatosis and The Glutamine-ammonia-urea Cycle Axismentioning

confidence: 99%

Section: Steatosis and The Glutamine-ammonia-urea Cycle Axismentioning

confidence: 99%

See 3 more Smart Citations

Glutaminolysis-ammonia-urea Cycle Axis, Non-alcoholic Fatty Liver Disease Progression and Development of Novel Therapies

Rojas¹,

García-Lozano²,

Gil‐Gómez³

et al. 2022

J Clin Transl Hepatol

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Endoplasmic reticulum stress and autophagy dysregulation in alcoholic and non-alcoholic liver diseases

Kim

2020

Clin Mol Hepatol

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Alcoholic and non-alcoholic liver diseases begin from an imbalance in lipid metabolism in hepatocytes as the earliest response. Both liver diseases share common disease features and stages (i.e., steatosis, hepatitis, cirrhosis, and hepatocellular carcinoma). However, the two diseases have differential pathogenesis and clinical symptoms. Studies have elucidated the molecular basis underlying similarities and differences in the pathogenesis of the diseases; the factors contributing to the progression of liver diseases include depletion of sulfhydryl pools, enhanced levels of reactive oxygen and nitrogen intermediates, increased sensitivity of hepatocytes to toxic cytokines, mitochondrial dysfunction, and insulin resistance. Endoplasmic reticulum (ER) stress, which is caused by the accumulation of misfolded proteins and calcium depletion, contributes to the pathogenesis, often causing catastrophic cell death. Several studies have demonstrated a mechanism by which ER stress triggers liver disease progression. Autophagy is an evolutionarily conserved process that regulates organelle turnover and cellular energy balance through decomposing damaged organelles including mitochondria, misfolded proteins, and lipid droplets. Autophagy dysregulation also exacerbates liver diseases. Thus, autophagy-related molecules can be potential therapeutic targets for liver diseases. Since ER stress and autophagy are closely linked to each other, an understanding of the molecules, gene clusters, and networks engaged in these processes would be of help to find new remedies for alcoholic and non-alcoholic liver diseases. In this review, we summarize the recent findings and perspectives in the context of the molecular pathogenesis of the liver diseases.

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Targeting Hepatic Glutaminase 1 Ameliorates Non-Alcoholic Steatohepatitis by Restoring Disrupted Hepatic Very-Low Density Lipoproteins Triglyceride Assembly

Cited by 2 publications

References 54 publications

Glutaminolysis-ammonia-urea Cycle Axis, Non-alcoholic Fatty Liver Disease Progression and Development of Novel Therapies

Glutaminolysis-ammonia-urea Cycle Axis, Non-alcoholic Fatty Liver Disease Progression and Development of Novel Therapies

Endoplasmic reticulum stress and autophagy dysregulation in alcoholic and non-alcoholic liver diseases

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