Small Intestine but Not Liver Lysophosphatidylcholine Acyltransferase 3 (Lpcat3) Deficiency Has a Dominant Effect on Plasma Lipid Metabolism

Abstract

Lysophosphatidylcholine acyltransferase 3 (Lpcat3) is involved in phosphatidylcholine remodeling in the small intestine and liver. We investigated lipid metabolism in inducible intestine-specific and liver-specific Lpcat3 gene knock-out mice. We produced Lpcat3-Flox/villin-Cre-ER T2 mice, which were treated with tamoxifen (at days 1, 3, 5, and 7), to delete Lpcat3 specifically in the small intestine. At day 9 after the treatment, we found that Lpcat3 deficiency in enterocytes significantly reduced polyunsaturated phosphatidylcholines in the enterocyte plasma membrane and reduced Niemann-Pick C1-like 1 (NPC1L1), CD36, ATP-binding cassette transporter 1 (ABCA1), and ABCG8 levels on the membrane, thus significantly reducing lipid absorption, cholesterol secretion through apoB-dependent and apoB-independent pathways, and plasma triglyceride, cholesterol, and phospholipid levels, as well as body weight. Moreover, Lpcat3 deficiency does not cause significant lipid accumulation in the small intestine. We also utilized adenovirus-associated virus-Cre to deplete Lpcat3 in the liver. We found that liver deficiency only reduces plasma triglyceride levels but not other lipid levels. Furthermore, there is no significant lipid accumulation in the liver. Importantly, small intestine Lpcat3 deficiency has a much bigger effect on plasma lipid levels than that of liver deficiency. Thus, inhibition of small intestine Lpcat3 might constitute a novel approach for treating hyperlipidemia.The majority of lipids on the cell membrane as well as the plasma lipoproteins are phospholipids, in particular phosphatidylcholines (PCs) 2 (1, 2). Monounsaturated and saturated fatty acids are usually esterified at the sn-1 position of PCs, whereas polyunsaturated fatty acids are esterified at the sn-2 position (3). The asymmetric distribution of fatty acids at the sn-1 and sn-2 positions of PCs is maintained in part by a deacylationreacylation process known as the Lands cycle or PC remodeling (3, 4). One key enzyme in this remodeling is lysophosphatidylcholine acyltransferase (Lpcat), which utilizes lyso-PC and polyunsaturated acyl-CoA to produce sn-2 polyunsaturated PCs. There are four isoforms of this enzyme (5), and Lpcat3 is the major isoform in the small intestine and liver (6 -8).Lpcat3 is one of the downstream targets of liver X receptor (8) and peroxisome proliferator-activated receptor ␣ (6). Acute knockdown of Lpcat3 expression in the liver of genetically obese mice exacerbates lipid-induced endoplasmic reticulum (ER) stress (8). Moreover, global Lpcat3 knock-out (KO) mice exhibit neonatal lethality and have an abnormal small intestine (9, 10). Liver-specific deletion of Lpcat3 has no effect on ER stress but results in a reduction of plasma triglycerides and induction of hepatosteatosis under high fat feeding conditions (9). Because of neonatal lethality (non-inducible approach was utilized), only 1-week-old newborns were analyzed for the impact of intestine-specific Lpcat3 deficiency on lipid metabolism (9). Very recently, we found that...

The membrane‐bound O‐acyltransferase domain‐containing 7 variant rs641738 increases inflammation and fibrosis in chronic hepatitis B

“…Notably, recent reports consistently demonstrate that liverspecific gene deletion of the related Mboat5 (Lpcat3) exacerbates hepatic inflammation and macrophage infiltration, whereas it has no significant effect on lipid accumulation when mice are fed normal chow. (36,37) In toto, this suggests that inflammation is the driver for MBOAT7-mediated fibrosis, a hypothesis consistent with all published data. (3)(4)(5)(6) Interestingly, similar to earlier reports, (13,17) we show that neither PNPLA3 nor TM6SF2, both implicated in hepatic lipid trapping, had any significant influence on liver damage in CHB.…”

“…Furthermore, as positive control, both PNPLA3 and TM6SF2 had an association with steatosis in CHB, implying that the impact of rs641738 on steatosis is likely marginal. Notably, recent reports consistently demonstrate that liver‐specific gene deletion of the related Mboat5 ( Lpcat3 ) exacerbates hepatic inflammation and macrophage infiltration, whereas it has no significant effect on lipid accumulation when mice are fed normal chow . In toto , this suggests that inflammation is the driver for MBOAT7‐mediated fibrosis, a hypothesis consistent with all published data …”

Hyperlipidemia Determines Dysfunctional HDL Production and Impedes Cholesterol Efflux in the Small Intestine: Alleviation by Ginger Extract

“…The ABCA1 transporter is responsible for the formation of pre‐β HDL on the enterocytes basal side . In good agreement with Kabir et al., our results show that HL induces a fall of ABCA1 expression in the SI . In the present study, we have proven for the first time that the administration of GIN causes the increase of ABCA1 protein levels in the SI, and thus may contribute to the increased production of pre‐β HDL.…”

Intestinal phospholipid and lysophospholipid metabolism in cardiometabolic disease

“…Studies from the Tontonoz laboratory yielded similar results, with additional observations that identified a mechanism related to reduced production of arachidonoyl phospholipids and the remodeling of enterocyte plasma membrane phospholipid composition being the gatekeeper important for passive lipid absorption and chylomicron production [**11,**12]. Although results from these studies have led to the suggestion that inhibiting intestinal LPCAT3 activity may be a novel approach for treatment of dietary lipid-associated hyperlipidemia and metabolic disorders [**10,**12], the desirability of this strategy requires extensive and detailed exploration considering that intestinal LPCAT3 activity appears to be required for survival of mice on lipid-rich diets and its inactivation causes the undesirable effects of food intake cessation and starvation [**12]. …”

“…The Jiang laboratory showed that the lack of LPCAT3 expression lower plasma levels of cholesterol, phospholipid, and triglyceride due to reduced lipid absorption [9]. Subsequent studies from the same laboratory documented that the dominant effect of LPCAT3 deficiency on plasma lipid levels is due to its defective expression in the intestine while liver LPCAT3 deficiency only impacts on plasma triglyceride levels [**10]. Studies from the Tontonoz laboratory yielded similar results, with additional observations that identified a mechanism related to reduced production of arachidonoyl phospholipids and the remodeling of enterocyte plasma membrane phospholipid composition being the gatekeeper important for passive lipid absorption and chylomicron production [**11,**12].…”