Monoglyceride lipase deficiency affects hepatic cholesterol metabolism and lipid-dependent gut transit in ApoE−/− mice

Abstract

Monoglyceride lipase (MGL) hydrolyzes monoglycerides (MGs) to glycerol and fatty acids. Among various MG species MGL also degrades 2-arachidonoylglycerol (2-AG), the most abundant endocannabinoid and potent activator of cannabinoid receptors (CBR) 1 and 2. MGL-knockout (−/−) mice exhibit pronounced 2-AG accumulation, but lack central cannabimimetic effects due to CB1R desensitization. We have previously shown that MGL affects plaque stability in apolipoprotein E (ApoE)−/− mice, an established animal model for dyslipidemia and atherosclerosis. In the current study, we investigated functional consequences of MGL deficiency on lipid and energy metabolism in ApoE/MGL double knockout (DKO) mice. MGL deficiency affected hepatic cholesterol metabolism by causing increased cholesterol elimination via the biliary pathway. Moreover, DKO mice exhibit lipid-triggered delay in gastric emptying without major effects on overall triglyceride and cholesterol absorption. The observed phenotype of DKO mice is likely not a consequence of potentiated CB1R signaling but rather dependent on the activation of alternative signaling pathways. We conclude that MGL deficiency causes complex metabolic changes including cholesterol metabolism and regulation of gut transit independent of the endocannabinoid system.

Lack of monoacylglycerol lipase prevents hepatic steatosis by favoring lipid storage in adipose tissue and intestinal malabsorption

“…1G) with increased intestinal cholesterol (Chol) excretion (Abcg5) but unchanged Abcg8 and other lipid transporters Npc1l1, Srb1, and cluster of differentiation 36 (Cd36) (supplemental Fig. S1C) in accordance with a previous report (25). This indicates that reduced lipid absorption also contributes to decreased obesity in MGL / mice.…”

“…The discrepancy between diminished body and augmented adipose fat weight turned our attention to investigate intestinal malabsorption as a possible mechanistic explanation for our findings. Intestinal malabsorption was already described in a recent study, in which Vujic et al (25) crossed ApoE / with MGL / mice to potentiate the effects of disrupted lipid signaling and exacerbate hyperlipidemia. In addition, it was shown that delayed gastric emptying and reduced gut motility may contribute to reduced FA uptake and Chol absorption in double-KO animals (25).…”

“…Intestinal malabsorption was already described in a recent study, in which Vujic et al (25) crossed ApoE / with MGL / mice to potentiate the effects of disrupted lipid signaling and exacerbate hyperlipidemia. In addition, it was shown that delayed gastric emptying and reduced gut motility may contribute to reduced FA uptake and Chol absorption in double-KO animals (25). In line with this report, we also investigated intestinal fat absorption in our model and observed elevated FA content in the feces, which we confirmed with gas-chromatography analysis after sucrose polybehenate feeding, evidencing reduced lipid absorption in MGL / mice fed a WD.…”

“…In addition, we recently showed that MGL invalidation strongly decreases fibrogenesis due to autophagy-mediated antiinflammatory properties in macrophages (31). Moreover, MGL expression is increased in intestine and liver by HFD treatment, indicating a potential role of MGs in intestinal degradation and absorption (8,25,32). Taschler et al (8) found accumulation of several MG species after HFD challenge; interestingly, 18:2 and 20:4 MG accumulated in the liver as well as in the gWAT but not in the small intestine of MGL / mice.…”

Intestine-specific DGAT1 deficiency improves atherosclerosis in apolipoprotein E knockout mice by reducing systemic cholesterol burden

“…Fractional cholesterol absorption was assessed in chow diet-fed male mice as described [ 18 ]. Briefly, animals were gavaged with 100 μl corn oil containing 0.2% cholesterol, 0.2 μCi [ 3 H]sitostanol, and 0.1 μCi [ 14 C] cholesterol (both from ARC Inc, St. Louis, MO).…”