Olanzapine leads to nonalcoholic fatty liver disease through the apolipoprotein A5 pathway

Li, Rong; Zhu, Wenqiang; Huang, Pengfei; Yang, Yang; Luo, Fei; Dai, Wen; Shen, Li; Pei, Wenjing; Huang, Xiansheng

doi:10.1016/j.biopha.2021.111803

Cited by 19 publications

(21 citation statements)

References 44 publications

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“…These side effects have complicated schizophrenia treatment, leading to higher rates of adverse cardiovascular events. Rodents receiving olanzapine are also predisposed to NAFLD, as confirmed by other studies and our previous data 4 , 5 . In the current work, olanzapine treatment led to hepatic steatosis in vivo and in vitro, characterized by excessive hepatic lipid accumulation and increased intra-hepatocyte lipid droplets.…”

Section: Discussionsupporting

confidence: 88%

“…Remarkably, long-term treatment with olanzapine, one of the most used drugs for schizophrenia, dramatically increases the risk of obesity and metabolic dysregulation 3 . Therefore, olanzapine treatment confers susceptibility to NAFLD, as confirmed by previous preclinical studies and in vitro models 4 , 5 , including our own research. However, the pathogenesis of olanzapine-induced NAFLD remains poorly understood, and no optimal therapeutics have been established.…”

Section: Introductionsupporting

confidence: 84%

“…Four groups were included in the in vitro experiments: control group, 100 μM olanzapine group, 2 mM metformin group, and 100 μM olanzapine + 2 mM metformin group. Olanzapine was added to the medium at a final concentration of 100 μM based on the optimal concentration selected in previous experiments for 24 h 5 , and the final concentration of metformin was 2 mM. The DMSO treatment group served as the blank control group.…”

Section: Methodsmentioning

confidence: 99%

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Metformin Ameliorates Hepatic Steatosis induced by olanzapine through inhibiting LXRα/PCSK9 pathway

Zhu

Ding

Huang

et al. 2022

Sci Rep

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Studies have confirmed that olanzapine, the mainstay treatment for schizophrenia, triggers metabolic diseases, including non-alcoholic fatty liver disease (NAFLD). However, the etiology of olanzapine-induced NAFLD is poorly understood. Proprotein convertase subtilisin kexin type 9 (PCSK9) is involved in NAFLD pathogenesis, and metformin can significantly decrease circulating PCSK9. The purpose of this study was to investigate the role of PCSK9 and explore the therapeutic effect of metformin for olanzapine-associated NAFLD. Olanzapine significantly upregulated PCSK9 and promoted lipid accumulation in mouse livers and HepG2 and AML12 cells. Metformin ameliorated these pathological alterations. PCSK9 upstream regulator liver X receptor α (LXRα) was significantly upregulated in olanzapine-induced NAFLD. LXRα antagonist treatment and LXRα overexpression resulted in a decrease and increase of PCSK9, respectively. Hepatic lipogenesis-associated genes FAS and SCD1 were significantly upregulated in olanzapine-induced NAFLD mice and HepG2 cells overexpressing PCSK9, and genes related to lipid β-oxidation (SCAD and PPARα) were downregulated, while metformin reversed these changes. In addition, we found that LXRα overexpression compromised the effect of metformin on PCSK9 levels and intracellular lipid droplet formation. Taken together, our findings suggest that olanzapine enhances hepatic PCSK9 expression by upregulating LXRα, thereby increasing FAS and SCD1 expression as well as decreasing SCAD and PPARα, and promoting lipid accumulation, and, subsequently, NAFLD, which is ameliorated by metformin.

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Section: Discussionsupporting

confidence: 88%

Section: Introductionsupporting

confidence: 84%

Section: Methodsmentioning

confidence: 99%

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Metformin Ameliorates Hepatic Steatosis induced by olanzapine through inhibiting LXRα/PCSK9 pathway

Zhu

Ding

Huang

et al. 2022

Sci Rep

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“…Overall, serotonin seems to aggravate fibrosis and inflammation. This is also demonstrated by the increase of serotonin concentrations by selective serotonin reuptake inhibitors and a subsequently increase in NAFLD [97][98][99]. Even though melatonin is a downstream metabolite of serotonin, its effect seems to be contrary to the effect of serotonin, with melatonin exhibiting protective abilities against fibrosis and inflammation.…”

Section: Serotonin and Melatonin Pathwaysmentioning

confidence: 99%

Interactions between Tryptophan Metabolism, the Gut Microbiome and the Immune System as Potential Drivers of Non-Alcoholic Fatty Liver Disease (NAFLD) and Metabolic Diseases

2022

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The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing and therefore is its burden of disease as NALFD is a risk factor for cirrhosis and is associated with other metabolic conditions such as type II diabetes, obesity, dyslipidaemia and atherosclerosis. Linking these cardiometabolic diseases is a state of low-grade inflammation, with higher cytokines and c-reactive protein levels found in individuals with NAFLD, obesity and type II diabetes. A possible therapeutic target to decrease this state of low-grade inflammation is the metabolism of the essential amino-acid tryptophan. Its three main metabolic pathways (kynurenine pathway, indole pathway and serotonin/melatonin pathway) result in metabolites such as kynurenic acid, xanturenic acid, indole-3-propionic acid and serotonin/melatonin. The kynurenine pathway is regulated by indoleamine 2,3-dioxygenase (IDO), an enzyme that is upregulated by pro-inflammatory molecules such as INF, IL-6 and LPS. Higher activity of IDO is associated with increased inflammation and fibrosis in NAFLD, as well with increased glucose levels, obesity and atherosclerosis. On the other hand, increased concentrations of the indole pathway metabolites, regulated by the gut microbiome, seem to result in more favorable outcomes. This narrative review summarizes the interactions between tryptophan metabolism, the gut microbiome and the immune system as potential drivers of cardiometabolic diseases in NAFLD.

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“…Development of NAFLD has been associated with AA treatment in preclinical models and patient populations [ 35 , 36 , 37 , 38 ], and patients treated with AA medications have been reported to have significantly higher rates of iron-deficiency anemia [ 17 , 26 , 39 , 40 , 41 , 42 , 43 , 44 ] and obesity [ 12 , 13 , 14 , 15 ]. Despite these reports, pathophysiological mechanisms by which AA treatment can lead to NAFLD and disruptions in iron homeostasis remain virtually unexplored.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms Underlying Antipsychotic-Induced NAFLD and Iron Dysregulation: A Multi-Omic Approach

et al. 2022

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Atypical antipsychotic (AA) medications are widely prescribed for the treatment of psychiatric disorders, including schizophrenia, bipolar disorder and treatment-resistant depression. AA are associated with myriad metabolic and endocrine side effects, including systemic inflammation, weight gain, dyslipidemia and insulin resistance, all of which are associated with increased incidence of non-alcoholic fatty liver disease (NAFLD). NAFLD is highly prevalent in patients with mental illness, and AA have been shown to increase incidence of NAFLD pre-clinically and clinically. However, the underlying mechanisms have not been described. We mined multi-omic datasets from preclinical murine models of sub-chronic risperidone or olanzapine treatment, in vitro exposure of human cells to risperidone and psychiatric patients following onset of aripiprazole therapy focused on pathways associated with the pathophysiology of NAFLD, including iron accumulation, systemic inflammation and dyslipidemia. We identified numerous differentially expressed traits affecting these pathways conserved across study systems and AA medications. We used these findings to propose mechanisms for AA-associated development of NAFLD and dysregulated iron homeostasis.

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Olanzapine leads to nonalcoholic fatty liver disease through the apolipoprotein A5 pathway

Cited by 19 publications

References 44 publications

Metformin Ameliorates Hepatic Steatosis induced by olanzapine through inhibiting LXRα/PCSK9 pathway

Metformin Ameliorates Hepatic Steatosis induced by olanzapine through inhibiting LXRα/PCSK9 pathway

Interactions between Tryptophan Metabolism, the Gut Microbiome and the Immune System as Potential Drivers of Non-Alcoholic Fatty Liver Disease (NAFLD) and Metabolic Diseases

Mechanisms Underlying Antipsychotic-Induced NAFLD and Iron Dysregulation: A Multi-Omic Approach

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