Targeting Hepatic Glutaminase 1 Ameliorates Non-alcoholic Steatohepatitis by Restoring Very-Low-Density Lipoprotein Triglyceride Assembly

Simón, Jorge; Núñez-García, Maitane; Fernández-Tussy, Pablo; Barbier-Torres, Lucía; Fernández‐Ramos, David; Gómez‐Santos, Beatriz; Buqué, Xabier; Lopitz‐Otsoa, Fernando; Goikoetxea‐Usandizaga, Naroa; Serrano‐Maciá, Marina; Rodríguez-Agudo, Rubén; Bizkarguenaga, Maider; Zubiete-Franco, Imanol; Juan, Virginia Gutiérrez‐de; Cabrera, Diana; Alonso, Cristina; Iruzubieta, Paula; Romero–Gómez, Manuel; Liempd, Sebastiaan van; Castro, Azucena; Nogueiras, Rubén; Varela‐Rey, Marta; Falcón‐Pérez, Juan Manuel; Villa, Erica; Crespo, Javier; Lu, Shelly C.; Mato, José M.; Aspichueta, Patricia; Delgado, Teresa C.; Martínez‐Chantar, María Luz

doi:10.1016/j.cmet.2020.01.013

Cited by 84 publications

(72 citation statements)

References 82 publications

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“…For example, high-fat diet (HFD)-fed PEMT-deficient mice develop more severe hepatic inflammation and fibrosis, likely due to cholestasis [ 73 ]. Similarly, patients with histological NASH and methionine- and choline-deficient-fed mice [ 74 ] displayed increased hepatic glutaminase 1 (GLS1), which is associated with reduced PC synthesis. Inhibition of GLS1 in the methionine and choline-deficient diet mouse model reduced oxidative stress by limiting anaplerotic reactions for the tricarboxylic acid (TCA) cycle.…”

Section: Dyslipidemia: Linking Hepatic Lipid Metabolism and The Heartmentioning

confidence: 99%

“…Inhibition of GLS1 in the methionine and choline-deficient diet mouse model reduced oxidative stress by limiting anaplerotic reactions for the tricarboxylic acid (TCA) cycle. By reducing oxidative stress, serine was used preferentially in the 1 carbon cycle to generate methyl donors for use in the conversion of PE to PC and VLDL-TG output was consequently restored [ 74 ]. This study provides evidence that oxidative stress induced by hepatic lipid overload could indirectly impact the PC/PE balance, impacting hepatic VLDL-TG output ( Figure 2 ).…”

Section: Dyslipidemia: Linking Hepatic Lipid Metabolism and The Heartmentioning

confidence: 99%

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Dysregulated lipid metabolism links NAFLD to cardiovascular disease

Deprince

Haas

Staels

2020

Molecular Metabolism

281

161

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Background Non-alcoholic fatty liver disease (NAFLD) is rapidly becoming a global health problem. Cardiovascular diseases (CVD) are the most common cause of mortality in NAFLD patients. NAFLD and CVD share several common risk factors including obesity, insulin resistance, and type 2 diabetes (T2D). Atherogenic dyslipidemia, characterized by plasma hypertriglyceridemia, increased small dense low-density lipoprotein (LDL) particles, and decreased high-density lipoprotein cholesterol (HDL-C) levels, is often observed in NAFLD patients. Scope of review In this review, we highlight recent epidemiological studies evaluating the link between NAFLD and CVD risk. We further focus on recent mechanistic insights into the links between NAFLD and altered lipoprotein metabolism. We also discuss current therapeutic strategies for NAFLD and their potential impact on NAFLD-associated CVD risk. Major conclusions Alterations in hepatic lipid and lipoprotein metabolism are major contributing factors to the increased CVD risk in NAFLD patients, and many promising NASH therapies in development also improve dyslipidemia in clinical trials.

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Section: Dyslipidemia: Linking Hepatic Lipid Metabolism and The Heartmentioning

confidence: 99%

Section: Dyslipidemia: Linking Hepatic Lipid Metabolism and The Heartmentioning

confidence: 99%

Dysregulated lipid metabolism links NAFLD to cardiovascular disease

Deprince

Haas

Staels

2020

Molecular Metabolism

281

161

View full text Add to dashboard Cite

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“…In methionine choline-deficient (MCD) diet-fed mice, GLS1 inhibition decreases hepatic TG accumulation by restoring VLDL TG export and diminishes oxidative stress by lowering ROS production. GLS1 deficiency in this model is also associated with decreased lipid peroxidation [ 234 ]. Paraoxonase-1 is a liver antioxidant enzyme that hydrolyses peroxide and lactones associated with lipoproteins.…”

Section: Role Of Oxidative Stress In Nafld Pathogenesismentioning

confidence: 99%

Oxidative Stress in NAFLD: Role of Nutrients and Food Contaminants

et al. 2020

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Non-alcoholic fatty liver disease (NAFLD) is often the hepatic expression of metabolic syndrome and its comorbidities that comprise, among others, obesity and insulin-resistance. NAFLD involves a large spectrum of clinical conditions. These range from steatosis, a benign liver disorder characterized by the accumulation of fat in hepatocytes, to non-alcoholic steatohepatitis (NASH), which is characterized by inflammation, hepatocyte damage, and liver fibrosis. NASH can further progress to cirrhosis and hepatocellular carcinoma. The etiology of NAFLD involves both genetic and environmental factors, including an unhealthy lifestyle. Of note, unhealthy eating is clearly associated with NAFLD development and progression to NASH. Both macronutrients (sugars, lipids, proteins) and micronutrients (vitamins, phytoingredients, antioxidants) affect NAFLD pathogenesis. Furthermore, some evidence indicates disruption of metabolic homeostasis by food contaminants, some of which are risk factor candidates in NAFLD. At the molecular level, several models have been proposed for the pathogenesis of NAFLD. Most importantly, oxidative stress and mitochondrial damage have been reported to be causative in NAFLD initiation and progression. The aim of this review is to provide an overview of the contribution of nutrients and food contaminants, especially pesticides, to oxidative stress and how they may influence NAFLD pathogenesis.

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“…The liver plays a key role in the metabolism of all biomolecules, but perturbations in lipid balance lead to the development of steatosis. In NAFLD, the genetic background or nutritional imbalances lead to a downregulation of the pathways involved in hepatic lipid clearance: (i) very-low-density lipoprotein (VLDL) secretion and (ii) fatty acid oxidation (FAO) or an upregulation in those that promote hepatic lipid content as (iii) de novo lipogenesis (DNL) and (iv) fatty acid (FA) uptake [ 8 ]. Although steatosis is usually considered a “brand” condition, chronic abnormal lipid deposition together with other hepatic insults or even other events beyond the liver, that include, for example, gut dysbiosis and adipose tissue inflammation, contribute to the development of NASH.…”

Section: Introductionmentioning

confidence: 99%

Magnesium, Little Known But Possibly Relevant: A Link between NASH and Related Comorbidities

et al. 2021

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Non-alcoholic steatohepatitis (NASH) is characterized by an abnormal hepatic lipid accumulation accompanied by a necro-inflammatory process and a fibrotic response. It comprises from 10% to 30% of cases of patients with non-alcoholic liver disease, which is a global health problem affecting around a quarter of the worldwide population. Nevertheless, the development of NASH is often surrounded by a pathological context with other comorbidities, such as cardiovascular diseases, obesity, insulin resistance or type 2 diabetes mellitus. Dietary imbalances are increasingly recognized as the root cause of these NASH-related comorbidities. In this context, a growing concern exists about whether magnesium consumption in the general population is sufficient. Hypomagnesemia is a hallmark of the aforementioned NASH comorbidities, and deficiencies in magnesium are also widely related to the triggering of complications that aggravate NASH or derived pathologies. Moreover, the supplementation of this cation has proved to reduce mortality from hepatic complications. In the present review, the role of magnesium in NASH and related comorbidities has been characterized, unraveling the relevance of maintaining the homeostasis of this cation for the correct functioning of the organism.

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Targeting Hepatic Glutaminase 1 Ameliorates Non-alcoholic Steatohepatitis by Restoring Very-Low-Density Lipoprotein Triglyceride Assembly

Abstract: Highlights d The high activity glutaminase isoform, GLS1, is augmented in NASH d GLS1 inhibition reduces steatosis in NASH by increasing VLDL export d GLS1 inhibition diminishes oxidative stress in pre-clinical models of NASH d GLS1 targeting may be a valuable therapeutic approach in NASH

Cited by 84 publications

References 82 publications

Dysregulated lipid metabolism links NAFLD to cardiovascular disease

Dysregulated lipid metabolism links NAFLD to cardiovascular disease

Oxidative Stress in NAFLD: Role of Nutrients and Food Contaminants

Magnesium, Little Known But Possibly Relevant: A Link between NASH and Related Comorbidities

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