Off-target effects of the lysosomal acid lipase inhibitors Lalistat-1 and Lalistat-2 on neutral lipid hydrolases

Impact of (intestinal) LAL deficiency on lipid metabolism and macrophage infiltration

“…Acid CE hydrolase (CEH) and TG hydrolase (TGH) activities, reflecting the enzymatic action of LAL, were reduced by ∼ 80% and 30%, respectively, in enterocytes isolated from LAL KO mice ( Figure 1 B,C). To test the possibility that other enzymes besides LAL may hydrolyze CE at an acidic pH, we included the inhibitor Lalistat 2 (L2) [ 33 ] in the assay. L2 failed to further reduce acid CEH activity in enterocyte lysates from LAL KO mice, but efficiently reduced the activity of WT samples to KO levels, suggesting that LAL is the only enzyme in enterocytes that hydrolyzes CE and TG at acidic pH ( Figure 1 B,C).…”

Metabolic changes and propensity for inflammation, fibrosis, and cancer in livers of mice lacking lysosomal acid lipase

“…Neutral (pH 7) and acidic (pH 4.5) CE hydrolase (CEH) and TG hydrolase (TGH) activities in liver lysates were measured using radioactively labeled substrates as previously described ( 17 ) with minor modifications. Briefly, half of the largest liver lobe was lysed in lysis buffer supplemented with 1 mM dithiothreitol and a protease inhibitor cocktail.…”

Dysregulation of Placental Lipid Hydrolysis by High-Fat/High-Cholesterol Feeding and Gestational Diabetes Mellitus in Mice

“…Enzymatic activities were assessed as described previously [ 17 , 52 ]. Briefly, to determine acid CE and TG hydrolase activities, tissues were lysed in acid citrate buffer (containing 54% 100 mM citric acid monohydrate and 46% 100 mM trisodium citrate, dehydrated, pH 4.2).…”