Inhibiting Insulin Resistance and Accumulation of Triglycerides and Cholesterol in the Liver
Christophe Wiart in Medicinal Plants in Asia for Metabolic Syndrome, 2017
Osthol from the fruits of Cnidium monnieri (L.) Cusson given to spontaneously hypertensive rats at 0.05% of diet for 4 weeks lowered systolic blood pressure by approximately 15%.367 This supplementation increased hepatic expression of 3-hydroxy-3-methylglutaryl-CoA reductase, acyl CoA oxidase, liver X receptor α and decreased hepatic apolipoprotein C-II and apolipoprotein C-III.367 This prenylated coumarin from given to Kunming mice on high-fat diet, orally at a dose of 40 mg/kg/day for 6 weeks evoked a reduction of body weight from 47.1 to 45.2 g, lowered hepatic cholesterol, hepatic triglycerides, and hepatic free fatty acids.368 In the serum of treated animals, osthol (Figure 3.27) reduced total cholesterol from 2.2 to 1.7 mmol/L (normal value: 1.8 mmol/L), triglycerides from 1.2 to 0.9 mmol/L, and free fatty acids from 6543 to 3373 µmol/L (below normal value: 5699 µmol/L). This coumarin evoked a reduction of hepatic expression of sterol regulatory element-binding protein-1c by about 45% and its target fatty acid synthetase.368 This coumarin evoked a reduction of sterol regulatory element-binding protein-2 by 80% hence decreased low-density lipoprotein expression. This coumarin increased the expression of CYP7A1.368 One could infer that osthol antagonizes liver X receptor hence repression of sterol regulatory element-binding protein-1c and CYP7A1.
Fever In Inherited and Metabolic Disorders
Benedict Isaac, Serge Kernbaum, Michael Burke in Unexplained Fever, 2019
The increase in triglycerides in either or both of these particles (>1000 mg/dl), lead to lipemia retinalis, eruptive type of skin xanthomata, and attacks of acute pancreatitis, making this nosological entity easily recognized. The presence of “milky” appearing plasma, and an overlying creamy layer in refrigerated plasma obtained from a fasting patient, establish the correct diagnosis. Confirmation may be achieved through analysis of plasma triglycerides (>1000 mg/dl), cholesterol (within normal limits), plasma lipoproteins (elevated VLDL), and quantification of lipoprotein lipase and apolipoprotein C-II.19,20
Lipoprotein lipase deficiency/type I hyperlipoproteinemia
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop in Atlas of Inherited Metabolic Diseases, 2020
A distinct molecular abnormality in the lipoprotein lipase enzyme complex has been defined as a deficiency in the apolipoprotein C-II (apoC-II) activator of the complex [59–65]. These patients tend to present clinically later than those with classic lipoprotein lipase deficiency, in post-adolescence or adult life. The nature of the defect was suggested in the first patient who had displayed hyperlipemia and no activity of lipoprotein lipase, when the concentration of triglycerides fell sharply following a transfusion of blood for anemia. It was demonstrated that his plasma completely lacked apoC-II.
Angiopoietin-like proteins as therapeutic targets for cardiovascular disease: focus on lipid disorders
Published in Expert Opinion on Therapeutic Targets, 2020
Marco Bruno Morelli, Christopher Chavez, Gaetano Santulli
The trans-endothelial transport of LPL toward the capillary lumen is mediated by Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1), which has a high binding affinity for LPL [21–23]. The Heparan Sulfated Peptidoglycan (HSPG) binds LPL in the interstitial space, allowing the interaction with GPIHBP1 [24]. Numerous studies based on protein lipase X-ray crystallography and molecular modeling were conducted from the middle of the ’90s until now: Van Tilbeurgh et al. in 1994 published the first LPL structural model obtained from pancreatic lipase crystals [25]; LPL in its activated state is a 55-kDa noncovalently-bound homodimer with a head-to-tail orientation [22,25,26]. The hydrolysis of TGs present in TG-rich lipoproteins occurs through the interaction with Apolipoprotein C2, a key component of both VLDL and chylomicrons [27]. Modeling studies indicate that the catalytic site of LPL – a conserved Ser132, Asp156, and His241 sequence in the N-terminal domain – is covered by a mobile subdomain lid (or flap) [25,28] that controls catalytic activity and can be opened by the binding of chylomicrons and VLDL to the C-terminus of LPL [29]. Recently, Birrane et al. have shown the structure of LPL complexed with GPIHBP1 using X-ray crystallography [26]. Such analysis has allowed to define how GPIHBP1 interacts, anchors, and stabilizes LPL [26].
Identifying suspected familial chylomicronemia syndrome
Published in Baylor University Medical Center Proceedings, 2018
Ronak Rengarajan, Peter A. McCullough, Anima Chowdhury, Kristen M. Tecson
Excessively high triglycerides (>1000 mg/dL) typically reveal the presence of abnormalities in the lipolysis pathway; determining the etiology of these elevated triglycerides is challenging, however. FCS has a genetic basis resulting from a loss-of-function mutation in genes involved in lipolysis. Five main genes have been implicated in FCS, with over 100 mutations. The most common cause is a mutation of the lipoprotein lipase (LPL) gene itself, present in over 80% of genetically confirmed FCS cases.3,8 The frequency of carriers of LPL deficiency is estimated to be around 1 in 500.9,10 Such mutations can cause a presentation of illness during infancy. Less common mutations of the apolipoprotein C2 (APOC2) gene can cause presentation in childhood. Conversely, patients with glycosylphosphatidylinositol anchored high-density lipoprotein binding protein 1, apolipoprotein A5, and lipase maturation factor 1 mutations typically show signs of chylomicronemia in late adulthood (Figure 3).2
FXR modulators for enterohepatic and metabolic diseases
Published in Expert Opinion on Therapeutic Patents, 2018
Hong Wang, Qingxian He, Guangji Wang, Xiaowei Xu, Haiping Hao
Fxr−/− mice are characterized with enhanced serum cholesterol and triglyceride levels, suggesting that FXR plays essential role in lipid homeostasis through regulating cholesterol catabolism, transport and lipoprotein metabolism [6] (Figure 1). The ATP binding cassette subfamily G member 5/8 (ABCG5/G8), which mediate the intestinal and biliary secretion of cholesterol, is induced upon FXR activation [11]. Apolipoprotein C-II (Apo C-II) and Apo C-III, activator or inhibit of lipoprotein lipase (LPL), are induced and repressed upon FXR activation, respectively [12]. In addition, FXR activation also controls genes involved in triglyceride synthesis and metabolism. Upon positive regulation on carboxylesterase 1 (CES1) and peroxisome proliferator-activated receptor α (PPARα) and negative regulation on sterol regulatory element-binding protein-1c (SREBP-1c), FXR activation reduces hepatic triglyceride levels [13–15]. Taken together, these investigations suggest that FXR activation lowers plasma and hepatic lipid levels via repressing hepatic lipogenesis and secretion as well as increasing the clearance of lipoproteins. However, HDL-C concentration is simultaneously decreased upon FXR agonism due to its repression on Apo A-I and induction on scavenger receptor type I B1 (SR-BI) [16]. Apart from its activation, reduced FXR expression in the liver was demonstrated to be in charge of hepatic steatosis in aging mice [17], suggesting the expression level of FXR also acts as determinant of lipid metabolism. FXR activation and/or overexpression are expected to reduce levels of liver and serum TG in conditions including obesity and non-alcoholic steatohepatitis (NASH).
Related Knowledge Centers
- Chylomicron
- Fatty Acid
- Hepatosplenomegaly
- Lipoprotein Lipase
- Protein
- Xanthoma
- Gene
- Very Low-Density Lipoprotein
- Hyperlipidemia
- Pancreatitis