Abstract
Human hepatic lipase (hHL) is mainly localized on the hepatocyte cell surface where it hydrolyzes lipids from remnant lipoproteins and high density lipoproteins and promotes their hepatic selective uptake. Furthermore, hepatic lipase (HL) is closely associated with obesity in multiple studies. Therefore, HL may play a key role on lipid homeostasis in liver and white adipose tissue (WAT). In the present study, we aimed to evaluate the effects of hHL expression on hepatic and white adipose triglyceride metabolism in vivo. Experiments were carried out in hHL transgenic and wild-type mice fed a Western-type diet. Triglyceride metabolism studies included β-oxidation and de novo lipogenesis in liver and WAT, hepatic triglyceride secretion, and adipose lipoprotein lipase (LPL)-mediated free fatty acid (FFA) lipolysis and influx. The expression of hHL promoted hepatic triglyceride accumulation and de novo lipogenesis without affecting triglyceride secretion, and this was associated with an upregulation of Srebf1 as well as the main genes controlling the synthesis of fatty acids. Transgenic mice also exhibited more adiposity and an increased LPL-mediated FFA influx into the WAT without affecting glucose tolerance. Our results demonstrate that hHL promoted hepatic steatosis in mice mainly by upregulating de novo lipogenesis. HL also upregulated WAT LPL and promoted triglyceride-rich lipoprotein hydrolysis and adipose FFA uptake. These data support the important role of hHL in regulating hepatic lipid homeostasis and confirm the broad cardiometabolic role of HL.
Highlights
Hepatic lipase (HL) is a lipase mainly secreted from the liver and localized mainly on the surface of liver sinusoidal capillaries [1]
For studying triglyceride metabolism under postprandial conditions, mice were administered an oral fat gavage consisting of an intragastric load of 150 μL of olive oil and euthanized after 90 minutes, except for hepatic triglyceride secretion studies, which use an inhibitor of lipolysis; assays were carried out under fasting conditions to avoid the accumulation of intestinal triglyceride-rich lipoproteins
Consistent with the macroscopic changes found in the liver, the expression of Human hepatic lipase (hHL) led to the development of steatosis as revealed by the increased liver weight (Fig 2A) and a higher hepatic lipid content, mainly by an increase of the triglyceride content (Fig 2B)
Summary
Hepatic lipase (HL) is a lipase mainly secreted from the liver and localized mainly on the surface of liver sinusoidal capillaries [1]. Hepatic steatosis is directly related to enhanced oxidative stress and lipotoxicity induced by excess fatty acids at the intracellular level [5]. HL activity positively correlated with the severity of steatosis in NAFLD patients, even after correcting for body mass index and homeostasis model assessment (HOMA) for the insulin resistance index [10]. Both liver HL activity and the amount of hepatic lipids were significantly reduced in morbidly obese subjects after bariatric surgery [11]
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