Abstract
Hormone-sensitive lipase (HSL) is believed to play an important role in the mobilization of fatty acids from triglycerides (TG), diglycerides, and cholesteryl esters in various tissues. Because HSL-mediated lipolysis of TG in adipose tissue (AT) directly feeds non-esterified fatty acids (NEFA) into the vascular system, the enzyme is expected to affect many metabolic processes including the metabolism of plasma lipids and lipoproteins. In the present study we examined these metabolic changes in induced mutant mouse lines that lack HSL expression (HSL-ko mice). During fasting, when HSL is normally strongly induced in AT, HSL-ko animals exhibited markedly decreased plasma concentrations of NEFA (-40%) and TG (-63%), whereas total cholesterol and HDL cholesterol levels were increased (+34%). Except for the increased HDL cholesterol concentrations, these differences were not observed in fed animals, in which HSL activity is generally low. Decreased plasma TG levels in fasted HSL-ko mice were mainly caused by decreased hepatic very low density lipid lipoprotein (VLDL) synthesis as a result of decreased NEFA transport from the periphery to the liver. Reduced NEFA transport was also indicated by a depletion of hepatic TG stores (-90%) and strongly decreased ketone body concentrations in plasma (-80%). Decreased plasma NEFA and TG levels in fasted HSL-ko mice were associated with increased fractional catabolic rates of VLDL-TG and an induction of the tissue-specific lipoprotein lipase (LPL) activity in cardiac muscle, skeletal muscle, and white AT. In brown AT, LPL activity was decreased. Both increased VLDL fractional catabolic rates and increased LPL activity in muscle were unable to provide the heart with sufficient NEFA, which led to decreased tissue TG levels in cardiac muscle. Our results demonstrate that HSL deficiency markedly affects the metabolism of TG-rich lipoproteins by the coordinate down-regulation of VLDL synthesis and up-regulation of LPL in muscle and white adipose tissue. These changes result in an "anti-atherogenic" lipoprotein profile.
Highlights
In mammals, white adipose tissue (WAT)1 is the most important storage organ of TG
In brown AT, lipoprotein lipase (LPL) activity was decreased. Both increased very low density lipid lipoprotein (VLDL) fractional catabolic rates and increased LPL activity in muscle were unable to provide the heart with sufficient non-esterified fatty acids (NEFA), which led to decreased tissue TG levels in cardiac muscle
Our results demonstrate that Hormone-sensitive lipase (HSL) deficiency markedly affects the metabolism of TG-rich lipoproteins by the coordinate down-regulation of VLDL synthesis and up-regulation of LPL in muscle and white adipose tissue
Summary
Animals—HSL-ko mice were generated by targeted homologous recombination as previously described [24]. Cryosections and TG Determination in the Liver and Cardiac Muscle—After perfusion with 0.9% NaCl for removal of blood lipids, organs from fed and fasted mice were instantly frozen in liquid nitrogen. Anesthetized fasted mice were injected intravenously with 500 mg of Triton WR1339 (Sigma)/kg of body weight as a 15 g/dl solution in 0.9% NaCl. Blood samples were drawn before injection of Triton WR1339 and 1, 2, 3, and 4 h after injection. Anesthetized mice were injected intravenously with 400,000 cpm of radiolabeled VLDL, and the disappearance of radioactivity was determined from plasma samples drawn 0.5, 1, 2, 3, 5, 10, 15, and 30 min after the injection. Analysis of LPL mRNA in WAT, BAT, and Cardiac Muscle— Tissues from fasted mice were surgically removed, weighed, and subsequently frozen in liquid nitrogen. Statistical significance was tested using two-tailed Student’s t test
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