Lisa Longato1, Ming Tong, Jack R Wands, Suzanne M de la Monte. 1. Departments of Medicine, Pathology and Neurology, Divisions of Gastroenterology and Neuropathology, and the Liver Research Center, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.
Abstract
AIM: Non-alcoholic fatty liver disease (NAFLD) is an insulin resistance disease that can progress to cirrhosis and liver failure. We hypothesized that in NAFLD, insulin resistance dysregulates lipid metabolism, increasing production of cytotoxic lipids including ceramides, which exacerbate hepatic insulin resistance and injury. METHODS: Long Evans rats were pair-fed low (LFD) or high (HFD) fat diets for 8 weeks. Livers were used to measure lipids, gene expression, insulin receptor binding, integrity of insulin signaling, and pro-inflammatory cytokines. In vitro experiments characterized effects of ceramides on Huh7 cell viability, mitochondrial function, and insulin signaling. RESULTS: High fat diet feeding caused NAFLD with peripheral and hepatic insulin resistance, increased hepatic expression of pro-ceramide genes, sphingomyelinase activity, and lipid peroxidation, and increased serum ceramide. Ceramide treatment impaired Huh7 cell viability, mitochondrial function, and insulin signaling. CONCLUSIONS: Increased hepatic ceramide generation and release may mediate both hepatic and peripheral insulin resistance in NAFLD.
AIM: Non-alcoholic fatty liver disease (NAFLD) is an insulin resistance disease that can progress to cirrhosis and liver failure. We hypothesized that in NAFLD, insulin resistance dysregulates lipid metabolism, increasing production of cytotoxic lipids including ceramides, which exacerbate hepatic insulin resistance and injury. METHODS: Long Evans rats were pair-fed low (LFD) or high (HFD) fat diets for 8 weeks. Livers were used to measure lipids, gene expression, insulin receptor binding, integrity of insulin signaling, and pro-inflammatory cytokines. In vitro experiments characterized effects of ceramides on Huh7 cell viability, mitochondrial function, and insulin signaling. RESULTS: High fat diet feeding caused NAFLD with peripheral and hepatic insulin resistance, increased hepatic expression of pro-ceramide genes, sphingomyelinase activity, and lipid peroxidation, and increased serum ceramide. Ceramide treatment impaired Huh7 cell viability, mitochondrial function, and insulin signaling. CONCLUSIONS: Increased hepatic ceramide generation and release may mediate both hepatic and peripheral insulin resistance in NAFLD.
Authors: Dario Greco; Anna Kotronen; Jukka Westerbacka; Oscar Puig; Perttu Arkkila; Tuula Kiviluoto; Saara Laitinen; Maria Kolak; Rachel M Fisher; Anders Hamsten; Petri Auvinen; Hannele Yki-Järvinen Journal: Am J Physiol Gastrointest Liver Physiol Date: 2008-04-03 Impact factor: 4.052
Authors: M Chiara Cantarini; Suzanne M de la Monte; Maoyin Pang; Ming Tong; Antonia D'Errico; Franco Trevisani; Jack R Wands Journal: Hepatology Date: 2006-08 Impact factor: 17.425
Authors: David Rojo; María J Gosalbes; Rafaela Ferrari; Ana E Pérez-Cobas; Ester Hernández; Rosa Oltra; Javier Buesa; Amparo Latorre; Coral Barbas; Manuel Ferrer; Andrés Moya Journal: ISME J Date: 2015-03-10 Impact factor: 10.302
Authors: Resat Cinar; Grzegorz Godlewski; Jie Liu; Joseph Tam; Tony Jourdan; Bani Mukhopadhyay; Judith Harvey-White; George Kunos Journal: Hepatology Date: 2013-11-18 Impact factor: 17.425
Authors: Teresa Ramirez; Lisa Longato; Miroslav Dostalek; Ming Tong; Jack R Wands; Suzanne M de la Monte Journal: Alcohol Alcohol Date: 2012-09-20 Impact factor: 2.826
Authors: Amar B Singh; Chin Fung K Kan; Fredric B Kraemer; Raymond A Sobel; Jingwen Liu Journal: Am J Physiol Endocrinol Metab Date: 2019-02-05 Impact factor: 4.310
Authors: Teresa Ramirez; Ming Tong; William Cy Chen; Quynh-Giao Nguyen; Jack R Wands; Suzanne M de la Monte Journal: J Gastroenterol Hepatol Date: 2013-01 Impact factor: 4.029