1. Hepatic stearoyl-CoA desaturase-1 deficiency induces fibrosis and hepatocellular carcinoma-related gene activation under a high carbohydrate low fat diet.
- Author
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Ntambi JN, Kalyesubula M, Cootway D, Lewis SA, Phang YX, Liu Z, O'Neill LM, Lefers L, Huff H, Miller JR, Pegkou Christofi V, Anderson E, Aljohani A, Mutebi F, Dutta M, Patterson A, and Ntambi JM
- Subjects
- Animals, Mice, Liver metabolism, Liver pathology, Lipogenesis genetics, Osteopontin genetics, Osteopontin metabolism, Osteopontin deficiency, Mice, Knockout, Male, Mice, Inbred C57BL, Dietary Carbohydrates administration & dosage, Dietary Carbohydrates adverse effects, Humans, Stearoyl-CoA Desaturase genetics, Stearoyl-CoA Desaturase metabolism, Stearoyl-CoA Desaturase deficiency, Carcinoma, Hepatocellular genetics, Carcinoma, Hepatocellular metabolism, Carcinoma, Hepatocellular pathology, Carcinoma, Hepatocellular etiology, Liver Neoplasms genetics, Liver Neoplasms metabolism, Liver Neoplasms pathology, Liver Neoplasms etiology, Liver Cirrhosis genetics, Liver Cirrhosis metabolism, Liver Cirrhosis pathology, Liver Cirrhosis etiology
- Abstract
Stearoyl-CoA desaturase-1 (SCD1) is a pivotal enzyme in lipogenesis, which catalyzes the synthesis of monounsaturated fatty acids (MUFA) from saturated fatty acids, whose ablation downregulates lipid synthesis, preventing steatosis and obesity. Yet deletion of SCD1 promotes hepatic inflammation and endoplasmic reticulum stress, raising the question of whether hepatic SCD1 deficiency promotes further liver damage, including fibrosis. To delineate whether SCD1 deficiency predisposes the liver to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC), we employed in vivo SCD1 deficient global and liver-specific mouse models fed a high carbohydrate low-fat diet and in vitro established AML12 mouse cells. The absence of liver SCD1 remarkably increased the saturation of liver lipid species, as indicated by lipidomic analysis, and led to hepatic fibrosis. Consistently, SCD1 deficiency promoted hepatic gene expression related to fibrosis, cirrhosis, and HCC. Deletion of SCD1 increased the circulating levels of Osteopontin, known to be increased in fibrosis, and alpha-fetoprotein, often used as an early marker and a prognostic marker for patients with HCC. De novo lipogenesis or dietary supplementation of oleate, an SCD1-generated MUFA, restored the gene expression related to fibrosis, cirrhosis, and HCC. Although SCD1 deficient mice are protected against obesity and fatty liver, our results show that MUFA deprivation results in liver injury, including fibrosis, thus providing novel insights between MUFA insufficiency and pathways leading to fibrosis, cirrhosis, and HCC under lean non-steatotic conditions., Competing Interests: Declaration of competing interest The authors who participated in this study declare no conflicts of interest regarding this work., (Copyright © 2024 Elsevier B.V. All rights reserved.)
- Published
- 2024
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