Downregulation of hepatic lipopolysaccharide binding protein improves lipogenesis-induced liver lipid accumulation.
Por:
Latorre J, Díaz-Trelles R, Comas F, Gavaldà-Navarro A, Milbank E, Dragano N, Morón S, Mukthavaram R, Ortega F, Castells-Nobau A, Oliveras-Cañellas N, Ricart W, Karmali PP, Tachikawa K, Chivukula P, Villarroya-Gombau F, López M, Giralt M, Fernández-Real JM and Moreno-Navarrete JM
Publicada:
13 sep 2022
Ahead of Print:
5 ago 2022
Resumen:
Circulating lipopolysaccharide-binding protein (LBP) is increased in individuals with liver steatosis. We aimed to evaluate the possible impact of liver LBP downregulation using lipid nanoparticle-containing chemically modified LBP small interfering RNA (siRNA) (LNP-Lbp UNA-siRNA) on the development of fatty liver. Weekly LNP-Lbp UNA-siRNA was administered to mice fed a standard chow diet, a high-fat and high-sucrose diet, and a methionine- and choline-deficient diet (MCD). In mice fed a high-fat and high-sucrose diet, which displayed induced liver lipogenesis, LBP downregulation led to reduced liver lipid accumulation, lipogenesis (mainly stearoyl-coenzyme A desaturase 1 [Scd1]) and lipid peroxidation-associated oxidative stress markers. LNP-Lbp UNA-siRNA also resulted in significantly decreased blood glucose levels during an insulin tolerance test. In mice fed a standard chow diet or an MCD, in which liver lipogenesis was not induced or was inhibited (especially Scd1 mRNA), liver LBP downregulation did not impact on liver steatosis. The link between hepatocyte LBP and lipogenesis was further confirmed in palmitate-treated Hepa1-6 cells, in primary human hepatocytes, and in subjects with morbid obesity. Altogether, these data indicate that siRNA against liver Lbp mRNA constitutes a potential target therapy for obesity-associated fatty liver through the modulation of hepatic Scd1.
Filiaciones:
Latorre J:
Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), 17007 Girona, Spain
CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 28029, Madrid, Spain
Díaz-Trelles R:
Arcturus Therapeutics, San Diego, CA 92121, USA
Comas F:
Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), 17007 Girona, Spain
CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 28029, Madrid, Spain
Gavaldà-Navarro A:
CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 28029, Madrid, Spain
Department of Biochemistry and Molecular Biomedicine, Faculty of Biology and Institute of Biomedicine (IBUB), University of Barcelona, CIBEROBN (CB06/03/025), 08028 Barcelona, Catalonia, Spain
Milbank E:
CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 28029, Madrid, Spain
NeurObesity Group, Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, 15782 Santiago de Compostela, Spain
Dragano N:
CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 28029, Madrid, Spain
NeurObesity Group, Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, 15782 Santiago de Compostela, Spain
Morón S:
Department of Biochemistry and Molecular Biomedicine, Faculty of Biology and Institute of Biomedicine (IBUB), University of Barcelona, CIBEROBN (CB06/03/025), 08028 Barcelona, Catalonia, Spain
Mukthavaram R:
Arcturus Therapeutics, San Diego, CA 92121, USA
Ortega F:
Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), 17007 Girona, Spain
CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 28029, Madrid, Spain
Castells-Nobau A:
Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), 17007 Girona, Spain
CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 28029, Madrid, Spain
Oliveras-Cañellas N:
Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), 17007 Girona, Spain
CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 28029, Madrid, Spain
Ricart W:
Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), 17007 Girona, Spain
CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 28029, Madrid, Spain
Karmali PP:
Arcturus Therapeutics, San Diego, CA 92121, USA
Tachikawa K:
Arcturus Therapeutics, San Diego, CA 92121, USA
Chivukula P:
Arcturus Therapeutics, San Diego, CA 92121, USA
Villarroya-Gombau F:
CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 28029, Madrid, Spain
Department of Biochemistry and Molecular Biomedicine, Faculty of Biology and Institute of Biomedicine (IBUB), University of Barcelona, CIBEROBN (CB06/03/025), 08028 Barcelona, Catalonia, Spain
López M:
CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 28029, Madrid, Spain
NeurObesity Group, Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, 15782 Santiago de Compostela, Spain
Giralt M:
CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 28029, Madrid, Spain
Department of Biochemistry and Molecular Biomedicine, Faculty of Biology and Institute of Biomedicine (IBUB), University of Barcelona, CIBEROBN (CB06/03/025), 08028 Barcelona, Catalonia, Spain
Fernández-Real JM:
Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), 17007 Girona, Spain
CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 28029, Madrid, Spain
Department of Medicine, University of Girona, 17003 Girona, Spain
Moreno-Navarrete JM:
Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), 17007 Girona, Spain
CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 28029, Madrid, Spain
Open Access
|