||Ectopic fat accumulation in the liver and glucose homeostasis
Takamura, Toshinari ,
Misu, Hirofumi ,
Musculoskeletal Disease Associated with Diabetes Mellitus
199 , 2016-01-01
Liver fat is associated not only with enhanced hepatic glucose production but also with skeletal muscle insulin resistance, supporting a central role of fatty liver in systemic insulin resistance and existence of a network between the liver and skeletal muscle. Palmitate and cholesterol act as toxic lipids to cause hepatic insulin resistance via mitochondria-derived oxidative stress. Obesity-mediated disruption in crosstalk among protein-, glucose- and lipid-metabolism pathways results in hepatic insulin resistance, enhanced gluconeogenesis and liver steatosis by impairing proteasome function. The liver plays as an endocrine organ to produce functional hepatokines and thereby mediates fatty liver-associated skeletal muscle insulin resistance through unique mechanisms. Selenoprotein P is upregulated through FoxOs and hyperglycemia and causes resistance to insulin, angiogenesis and exercise through reductive stress. LECT2 is upregulated in satiety through AMPK inactivation and contributes to the development of muscle insulin resistance and obesity by activating JNK and by impairing myogenesis, respectively. Therefore, overnutrition evokes remodeling of nutrient homeostasis by toxic lipids and proteasome dysfunction in the liver. The remodeling also results in the overproduction of hepatokines that disrupt inter-organ network leading to pathology of diabetes. © Springer Japan 2016.