Hepatic steatosis: a mediator of the metabolic syndrome. Lessons from animal models.
Epidemiological studies in humans, as well as experimental studies in animal models, have shown an association between visceral obesity and dyslipidemia, insulin resistance, and type 2 diabetes mellitus. Recently, attention has been focused on the excessive accumulation of triglycerides (TG) in the liver as part of this syndrome. In this review, important principles of the pathophysiological involvement of the liver in the metabolic syndrome obtained in rodent models are summarized. We focus on non-alcoholic causes of steatosis, because the animal experiments we refer to did not include alcohol as an experimental condition. In general, there is continuous cycling and redistribution of non-oxidized fatty acids between different organs. The amount of TG in an intrinsically normal liver is not fixed but can readily be increased by nutritional, metabolic, and endocrine interactions involving TG/free fatty acid (FFA) partitioning and TG/FFA metabolism. Several lines of evidence indicate that hepatic TG accumulation is also a causative factor involved in hepatic insulin resistance. Complex interactions between endocrine, metabolic, and transcriptional pathways are involved in TG-induced hepatic insulin resistance. Therefore, the liver participates passively and actively in the metabolic derangements of the metabolic syndrome. We speculate that similar mechanisms may also be involved in human pathophysiology.
den Boer
M
M
TNO Prevention and Health, Gaubius Laboratory Leiden, Leiden, The Netherlands.
Voshol
P J
PJ
Kuipers
F
F
Havekes
L M
LM
Romijn
J A
JA
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000378:metabolism; D004285:Dogs; D005227:Fatty Acids / Q000378:metabolism*; D005234:Fatty Liver / Q000150:complications / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D006949:Hyperlipidemias / Q000150:complications / Q000378:metabolism; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism; D024821:Metabolic Syndrome / Q000150:complications / Q000378:metabolism*; D051379:Mice; D023421:Models, Animal; D008954:Models, Biological; D009765:Obesity / Q000150:complications / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D014158:Transcription, Genetic; D014280:Triglycerides / Q000378:metabolism*
D005227:Fatty Acids; D014280:Triglycerides; D005947:Glucose