ApoC-III inhibits clearance of triglyceride-rich lipoproteins through LDL family receptors

Gordts, Philip L.S.M.; Nock, Ryan; Son, Ni-Huiping; Ramms, Bastian; Lew, Irene; Gonzales, Jon C.; Thacker, Bryan E.; Basu, Debarati; Lee, Richard G.; Mullick, Adam E.; Graham, Mark; Goldberg, Ira J.; Crooke, Rosanne M.; Witztum, Joseph L.; Esko, Jeffrey D.

doi:10.1172/jci86610

Cited by 209 publications

(233 citation statements)

References 50 publications

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“…An increase of apoC-III by 50 M reduced the activity of LPL by about 30%. These results are in line with the recent results of Gordts et al (50), but are different from the data obtained with isolated chylomicrons as substrate for LPL where the inhibitory effect of apoC-III was stronger (51). In that case, complete inhibition was observed already by addition of apoC-III to a concentration of 10 M.…”

Section: Figsupporting

confidence: 63%

Lipoprotein lipase activity and interactions studied in human plasma by isothermal titration calorimetry

Reimund

Kovrov

Olivecrona

et al. 2017

Journal of Lipid Research

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LPL is produced and secreted from parenchymal cells like adipocytes and myocytes for transport to the luminal side of the endothelium via interaction with the glycosylphosphatidylinositol-anchored high density lipoprotein binding protein 1 (GPIHBP1) (8). Several plasma components have been shown to directly or indirectly modulate the activity of LPL. apoC-II and apoA-V increase the activity of LPL, while apoC-I, apoC-III, angiopoietin-like protein (ANGPTL)3, ANGPTL4, and ANGPTL8 decrease the activity (1, 9). The expression of each of these proteins depends on nutritional and hormonal factors, so that lipid uptake in tissues to a large extent is regulated by posttranslational effects on LPL (1, 9). It is possible that the macromolecular environment in plasma itself may be an influence on the interaction of LPL with its ligands. The protein concentration of plasma (80 g/l) has been shown to cause significant crowding effects (10). It is also possible that some plasma regulators of LPL activity have not been identified yet.LPL activity can be measured in vitro by using artificial, usually emulsified, systems of radiolabeled, fluorogenic, or chromogenic substrates, or isolated triglyceride-rich lipoproteins (TRLs). The reaction products are detected at certain time points by chemical quantification or by determination of radioactivity or fluorescence. These methods have been used to unravel important aspects of the action of LPL and also to quantitate the levels of LPL activity in cells and tissues. Only small amounts of LPL activity are normally present in the circulating blood (11). Therefore, intravenous injections of heparin are made to release LPL from its endothelial binding sites. Determination of LPL activity in postheparin plasma, using artificial substrate systems, is considered to give an estimation of the amount of active LPL at the vascular endothelium (12).Lack of a suitable technique for continuous monitoring of triglyceride hydrolysis in plasma has hampered the understanding of the action of LPL under physiological Abstract LPL hydrolyzes triglycerides in plasma lipoproteins. Due to the complex regulation mechanism, it has been difficult to mimic the physiological conditions under which LPL acts in vitro. We demonstrate that isothermal titration calorimetry (ITC), using human plasma as substrate, overcomes several limitations of previously used techniques. The high sensitivity of ITC allows continuous recording of the heat released during hydrolysis. Both initial rates and kinetics for complete hydrolysis of plasma lipids can be studied. The hydrolytic breakdown of plasma triglycerides by LPL at the capillary endothelium is a crucial event that contributes to control of the levels of triglycerides in plasma (1, 2). Many recent studies support the view that an elevated level of triglycerides in plasma is an independent risk factor for development of atherosclerosis (3-5). Therefore, the LPL system is considered to be an interesting target for drug design (6, 7). Education and Research Grant IUT 19-9,...

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Section: Figsupporting

confidence: 63%

Lipoprotein lipase activity and interactions studied in human plasma by isothermal titration calorimetry

Reimund

Kovrov

Olivecrona

et al. 2017

Journal of Lipid Research

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“…Although the predominant opinion had been that apoC-III raised plasma TGs primarily by inhibiting LPL activity (39), the recent demonstration that antisense-mediated suppression of apoC-III plasma levels in patients with familial chylomicronemia syndrome, who had no measurable LPL activity, nevertheless dramatically lowered their elevated plasma TG levels indicates that apoC-III lowers TGs in a non-LPL-dependent manner (40). This now appears to be inhibition by apoC-III of receptor-mediated hepatic clearance of TG-rich lipoproteins (41). Whether interfering with apoC-III production or activity could prevent CHD in individuals with milder TG elevations remains to be proven.…”

Section: Regulating Lpl In Its Wheelhouse: Apolipoproteinsmentioning

confidence: 99%

Multidimensional regulation of lipoprotein lipase: impact on biochemical and cardiovascular phenotypes

Hegele

2016

Journal of Lipid Research

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“…Elevated APOC3 levels also perturb hepatic uptake and clearance of TGrich lipoprotein remnants (15,16). This action is mediated by the low density lipoprotein (LDL) family receptors independently of LPL (17). Apart from its extracellular functions, APOC3 plays an intracellular role in promoting VLDL-TG secretion from the liver (18 -21).…”

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confidence: 99%

APOC3 Protein Is Not a Predisposing Factor for Fat-induced Nonalcoholic Fatty Liver Disease in Mice

Cheng

Yamauchi

Lee

et al. 2017

Journal of Biological Chemistry

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Edited by Jeffrey E. PessinNonalcoholic fatty liver disease (NAFLD), characterized by excessive fat accumulation in liver, is prevalent in obesity. Genetic factors that link obesity to NAFLD remain obscure. Apolipoprotein C3 (APOC3) is a lipid-binding protein with a pivotal role in triglyceride metabolism. Humans with APOC3 gain-of-function mutations and mice with APOC3 overproduction are associated with hypertriglyceridemia. Nonetheless, it remains controversial whether APOC3 is culpable for diet-induced NAFLD. To address this fundamental issue, we fed APOC3-transgenic and wild-type littermates a high fructose diet or high fat diet, followed by determination of the effect of APOC3 on hepatic lipid metabolism and inflammation and the progression of NAFLD. To gain mechanistic insight into NAFLD, we determined the impact of APOC3 on hepatic triglyceride synthesis and secretion versus fatty acid oxidation. APOC3-transgenic mice were hypertriglyceridemic, culminating in marked elevation of triglycerides, cholesterols, and nonesterified fatty acids in plasma. Despite the prevailing hypertriglyceridemia, APOC3-transgenic mice, relative to wild-type littermates, had similar weight gain and hepatic lipid content without alterations in hepatic expression of key genes involved in triglyceride synthesis and secretion and fatty acid oxidation. APOC3-transgenic and wild-type mice had similar Kupffer cell content without alterations in hepatic expression of pro-and anti-inflammatory cytokines. APOC3 neither exacerbated dietinduced adiposity nor aggravated the degree of steatosis in high fructose or high fat-fed APOC3-transgenic mice. These effects ensued independently of weight gain even after 10-month high fat feeding. We concluded that APOC3, whose dysregulation is liable for hypertriglyceridemia, is not a predisposing factor for linking overnutrition to NAFLD in obesity. Nonalcoholic fatty liver disease (NAFLD)4 is characterized by excessive lipid deposition in the liver of subjects with little alcohol consumption. Patients with NAFLD are at heightened risk of developing steatohepatitis with potential complications of fibrosis and cirrhosis (1-4). Currently, NAFLD affects about 30% of the general population, and its prevalence is increasing along with the rising epidemic of obesity in both adults and children (1, 5-10). Although it is known that NAFLD results from increased lipogenesis and decreased fatty acid oxidation in the liver, accompanied often by hepatic overproduction of TG-rich very low density lipoprotein (VLDL-TG), genetic factors that tip the balance of these three intertwining pathways in hepatic lipid metabolism at the expense of NAFLD are incompletely characterized.Apolipoprotein C3 (APOC3) (79 amino acids in length) is one of the most abundant apolipoproteins in the blood, where it is present as an exchangeable moiety between high density lipoproteins (HDLs) and triglyceride (TG)-rich particles, such as VLDL and chylomicrons (11). Secreted mainly from the liver and to a lesser extent from the intestine, AP...

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ApoC-III inhibits clearance of triglyceride-rich lipoproteins through LDL family receptors

Cited by 209 publications

References 50 publications

Lipoprotein lipase activity and interactions studied in human plasma by isothermal titration calorimetry

Lipoprotein lipase activity and interactions studied in human plasma by isothermal titration calorimetry

Multidimensional regulation of lipoprotein lipase: impact on biochemical and cardiovascular phenotypes

APOC3 Protein Is Not a Predisposing Factor for Fat-induced Nonalcoholic Fatty Liver Disease in Mice

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