Molecular mechanisms involved in hepatic steatosis and insulin resistance

Increased hepatic lipid content is associated with hepatic as well as whole-body insulin resistance and is typical for individuals with type 2 diabetes mellitus. However, whether insulin resistance causes hepatic steatosis or whether hepatic steatosis per se reduces insulin sensitivity remains unclear. Multiple metabolic pathways lead to the development of hepatic steatosis, including enhanced free fatty acid release from adipose tissues (lipolysis), increased de novo fatty acid synthesis (lipogenesis), decreased mitochondrial β-oxidation and decreased very low-density lipoprotein secretion. Although the molecular mechanisms leading to the development of hepatic steatosis in the pathogenesis of type 2 diabetes mellitus are complex, several recent animal models have shown that modulating important enzymes involved in hepatic fatty acid and glycerolipid synthesis might be a key for treating hepatic insulin resistance. We highlight recent advances in the understanding of the molecular mechanisms leading to the development of hepatic steatosis and insulin resistance. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00111.x, 2011).