SCD1 deficiency protects mice against ethanol-induced liver injury

Lounis, Mohamed Amine; Escoula, Quentin; Veillette, Cathy; Bergeron, Karl-F.; Ntambi, James M.; Mounier, Cathérine

doi:10.1016/j.bbalip.2016.07.012

Cited by 30 publications

(23 citation statements)

References 42 publications

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“…During the 8-week feeding period, whereas food intake was similar in all groups, a significant decrease in body weight was observed in both EtOH-fed WT and Pxr-null mice, compared with their respective controls (Table 1) and consistent with what was observed by others (46). However, liver weight and liver-to-body weight ratios were not significantly different between the control and EtOH-fed groups of both genotypes (Table 1).…”

Section: Etoh Induces Lipid Accumulation In Wt But Not Pxr-null Micesupporting

confidence: 88%

Pregnane X receptor promotes ethanol-induced hepatosteatosis in mice

Choi

Neequaye

French

et al. 2018

Journal of Biological Chemistry

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The pregnane X receptor (PXR, NR1I2) is a xenobiotic-sensing nuclear receptor that modulates the metabolic response to drugs and toxic agents. Both PXR activation and deficiency promote hepatic triglyceride accumulation, a hallmark feature of alcoholic liver disease. However, the molecular mechanism of PXR-mediated activation of ethanol (EtOH)-induced steatosis is unclear. Here, using male wildtype (WT) and -null mice, we examined PXR-mediated regulation of chronic EtOH-induced hepatic lipid accumulation and hepatotoxicity. EtOH ingestion for 8 weeks significantly (1.8-fold) up-regulated mRNA levels in WT mice. The EtOH exposure also increased mRNAs encoding hepatic constitutive androstane receptor (3-fold) and its target, (220-fold), in a PXR-dependent manner. Furthermore, WT mice had higher serum EtOH levels and developed hepatic steatosis characterized by micro- and macrovesicular lipid accumulation. Consistent with the development of steatosis, lipogenic gene induction was significantly increased in WT mice, including sterol regulatory element-binding protein 1c target gene fatty-acid synthase (3.0-fold), early growth response-1 (3.2-fold), and TNFα (3.0-fold), whereas the expression of peroxisome proliferator-activated receptor α target genes was suppressed. Of note, PXR deficiency suppressed these changes and steatosis. Protein levels, but not mRNAs levels, of EtOH-metabolizing enzymes, including alcohol dehydrogenase 1, aldehyde dehydrogenase 1A1, and catalase, as well as the microsomal triglyceride transfer protein, involved in regulating lipid output were higher in-null than in WT mice. These findings establish that PXR signaling contributes to ALD development and suggest that PXR antagonists may provide a new approach for ALD therapy.

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Section: Etoh Induces Lipid Accumulation In Wt But Not Pxr-null Micesupporting

confidence: 88%

Pregnane X receptor promotes ethanol-induced hepatosteatosis in mice

Choi

Neequaye

French

et al. 2018

Journal of Biological Chemistry

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“…Promotion of the synthesis of monounsaturated fatty acids could play an important role in the development of steatosis and liver injury with chronic-plus-binge alcohol exposure [95]. Study on SCD1 knockout mice showed significant resistance to alcohol-induced hepatic inflammation in comparison to the control group, emphasizing the critical role of SCD1 in AH [52]. SCD1 activity can be measured indirectly by the palmitoleic acid to palmitic acid ratio via serum lipid measurements [52,96].…”

Section: Stearoyl-coa Desaturase 1 (Scd1)mentioning

confidence: 99%

“…Study on SCD1 knockout mice showed significant resistance to alcohol-induced hepatic inflammation in comparison to the control group, emphasizing the critical role of SCD1 in AH [52]. SCD1 activity can be measured indirectly by the palmitoleic acid to palmitic acid ratio via serum lipid measurements [52,96]. SCD1 remains as a possible therapeutic target that needs more clinical and translational investigations to elucidate its role in inhibiting the hepatic inflammation.…”

Section: Stearoyl-coa Desaturase 1 (Scd1)mentioning

confidence: 99%

Emerging Noninvasive Biomarkers, and Medical Management Strategies for Alcoholic Hepatitis: Present Understanding and Scope

Gala

Vatsalya

2020

Cells

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Alcohol use disorder is associated with a wide array of hepatic pathologies ranging from steatosis to alcoholic-related cirrhosis (AC), alcoholic hepatitis (AH), or hepatocellular carcinoma (HCC). Biomarkers are categorized into two main categories: biomarkers associated with alcohol consumption and biomarkers of alcoholic liver disease (ALD). No ideal biomarker has been identified to quantify the degree of hepatocyte death or severity of AH, even though numerous biomarkers have been associated with AH. This review provides information of some of the novel and latest biomarkers that are being investigated and have shown a substantial association with the degree and severity of liver injury and inflammation. Importantly, they can be measured noninvasively. In this manuscript, we consolidate the present understanding and prospects of these biomarkers; and their application in assessing the severity and progression of the alcoholic liver disease (ALD). We also review current and upcoming management options for AH.

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“…Stearoyl-CoA desaturase-1 (SCD1) is a delta-9 fatty acid desaturase that promotes the synthesis of mono-unsaturated fatty acids and has been found to play an important role in the development of steatosis and liver injury induced by chronic-plus-binge ethanol feeding 77 . Carboxylesterase 1 (CES1), a drug-metabolizing enzyme, has been shown to play an important role in the control of lipid metabolism 78 .…”

Section: New Insights Into the Underlying Mechanisms Of Chronic-plus-mentioning

confidence: 99%

Animal Models of Alcoholic Liver Disease: Pathogenesis and Clinical Relevance

et al. 2017

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Alcoholic liver disease (ALD), a leading cause of chronic liver injury worldwide, comprises a range of disorders including simple steatosis, steatohepatitis, cirrhosis, and hepatocellular carcinoma. Over the last five decades, many animal models that have been useful for the study of ALD pathogenesis have been developed. Recently, a chronic-plus-binge ethanol feeding model was reported. This model induces significant steatosis, hepatic neutrophil infiltration, and liver injury. A clinically relevant model of high-fat diet feeding plus binge ethanol was also developed, which highlights the risk of excessive binge drinking in obese/overweight individuals. All of these models recapitulate some features of the different stages of ALD and have been widely used by many investigators to study the pathogenesis of ALD and test therapeutic drugs/components. However, these models are somewhat variable, depending on mouse genetic background, ethanol dose, and animal facility environment. This review focuses on these models and discusses these variations and some methods to improve the feeding protocol. The pathogenesis, clinical relevance, and translational studies of these models are also discussed.

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SCD1 deficiency protects mice against ethanol-induced liver injury

Cited by 30 publications

References 42 publications

Pregnane X receptor promotes ethanol-induced hepatosteatosis in mice

Pregnane X receptor promotes ethanol-induced hepatosteatosis in mice

Emerging Noninvasive Biomarkers, and Medical Management Strategies for Alcoholic Hepatitis: Present Understanding and Scope

Animal Models of Alcoholic Liver Disease: Pathogenesis and Clinical Relevance

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