Hepatic lipase deficiency produces glucose intolerance, inflammation and hepatic steatosis

J Endocrinol. 2015 Dec;227(3):179-91. doi: 10.1530/JOE-15-0219. Epub 2015 Sep 30.


Metabolic syndrome and type 2 diabetes mellitus constitute a major problem to global health, and their incidence is increasing at an alarming rate. Non-alcoholic fatty liver disease, which affects up to 90% of obese people and nearly 70% of the overweight, is commonly associated with MetS characteristics such as obesity, insulin resistance, hypertension and dyslipidemia. In the present study, we demonstrate that hepatic lipase (HL)-inactivation in mice fed with a high-fat, high-cholesterol diet produced dyslipidemia including hypercholesterolemia, hypertriglyceridemia and increased non-esterified fatty acid levels. These changes were accompanied by glucose intolerance, pancreatic and hepatic inflammation and steatosis. In addition, compared with WT mice, HL(-/-) mice exhibited enhanced circulating MCP1 levels, monocytosis and higher percentage of CD4+Th17+ cells. Consistent with increased inflammation, livers from HL(-/-) mice had augmented activation of the stress SAPK/JNK- and p38-pathways compared with the activation levels of the kinases in livers from WT mice. Analysis of HL(-/-) and WT mice fed regular chow diet showed dyslipidemia and glucose intolerance in HL(-/-) mice without any other changes in inflammation or hepatic steatosis. Altogether, these results indicate that dyslipidemia induced by HL-deficiency in combination with a high-fat, high-cholesterol diet promotes hepatic steatosis and inflammation in mice which are, at least in part, mediated by the activation of the stress SAPK/JNK- and p38-pathways. Future studies are warranted to asses the viability of therapeutic strategies based on the modulation of these kinases to reduce hepatic steatosis associated to lipase dysfunction.

Keywords: glucose intolerance; inflammation; lipase; steatosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / metabolism
  • Chemokine CCL2 / blood
  • Diet, High-Fat
  • Dyslipidemias / genetics
  • Dyslipidemias / metabolism*
  • Glucose Intolerance / genetics
  • Glucose Intolerance / metabolism*
  • Inflammation / genetics
  • Inflammation / metabolism*
  • Insulin / metabolism
  • Insulin Resistance / physiology
  • Lipase / genetics
  • Lipase / metabolism*
  • Lipid Metabolism / genetics*
  • Lipids / blood
  • Liver / metabolism*
  • Mice
  • Mice, Knockout
  • Non-alcoholic Fatty Liver Disease / genetics
  • Non-alcoholic Fatty Liver Disease / metabolism*
  • Pancreas / metabolism


  • Blood Glucose
  • Ccl2 protein, mouse
  • Chemokine CCL2
  • Insulin
  • Lipids
  • Lipase
  • Lipc protein, mouse