Apolipoprotein C-III: From Pathophysiology to Pharmacology

Norata, Giuseppe Danilo; Tsimikas, Sotirios; Pirillo, Angela; Catapano, Alberico L.

doi:10.1016/j.tips.2015.07.001

Cited by 160 publications

(131 citation statements)

References 111 publications

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“…APOC3 modulates TG metabolism via at least three distinct mechanisms: by inhibiting LPL-and HLmediated TG hydrolysis, by promoting hepatic VLDL-TG production, and by retarding hepatic uptake and clearance of TGrich lipoprotein remnants. As a result, APOC3 dysregulation is associated with abnormal TG metabolism (31,33,(51)(52)(53)(54)(55)(56). Notwithstanding its importance in the pathogenesis of hypertriglyceridemia, its functional contribution to NAFLD remains obscure.…”

Section: Discussionmentioning

confidence: 99%

“…Antisense oligonucleotide-mediated reduction of plasma APOC3 levels results in significantly lower plasma TG levels in nonhuman primates as well as patients with familial chylomicronemia (29,30). Taken together, these data have revealed a causal relationship between APOC3 overproduction and hypertriglyceridemia, validating APOC3 as a potential target for the development of anti-hypertriglyceridemia therapy for lowering the cardiovascular risk (31,32).…”

mentioning

confidence: 85%

“…Although APOC3 is being targeted for the development of anti-hypertriglyceridemia therapy for reducing the cardiovascular risk (31,32), cautions must be exercised for applying such therapy in patients with established NAFLD. Given its intracellular role in facilitating VLDL-TG assembly and secretion (18 -21), APOC3 is probably an ill target for therapeutic intervention of NAFLD.…”

Section: Journal Of Biological Chemistry 3699mentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 85%

Section: Journal Of Biological Chemistry 3699mentioning

confidence: 99%

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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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“…62,63 though results are inconsistent. 64 Polymorphisms in APOCIII, a lipoprotein that is critical in triglyceride metabolism and is associated with increased cardiovascular risk, 65 have been reported in patients with cryptogenic stroke and PFO as well. 62 Antiphospholipid antibodies were not found to be a risk factor however.…”

Section: Medical Therapymentioning

confidence: 99%

Patent Foramen Ovale and Stroke

Sun

Homma

2016

Circ J

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Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp coalesce into a single orifice that becomes the foramen secundum. The septum secundum then forms via involution of the ventrocranial wall and overlaps with the foramen secundum. The septum secundum does not close fully and an oval-shaped opening remains, which becomes the foramen ovale. 17 Prior to birth, the fetus is dependent on the maternal circulation for oxygenation, as the immature fetal lungs do not yet participate in oxygen exchange. As such, the foramen ovale (as well as the ductus arteriosus), enables shunting of blood away from the pulmonary circulation. At birth, when the neonate's lungs begin to participate in oxygen exchange, there is a precipitous drop in the pulmonary vascular resistance and there is reversal of flow through both the foramen ovale and ductus arteriosus. 18 In approximately 75% of individuals, the foramen ovale closes within a few years while in the remaining others, it stays open permanently as a PFO. EpidemiologyThe prevalence of PFO in the healthy adult population ranges from 15% to 25% on echocardiography and 15-35% on autopsy studies. 1,2,19,20 Observational and autopsy studies have showed that the prevalence of detected PFOs is lower in older patients and that detected PFOs in older individuals tend to be larger. 1,19,20 Those studies, however, may be confounded by selection and detection bias because none of the longitudinal studies have demonstrated that individual PFOs change in size. The prevalence of PFOs is equal among men and women, though there may be race-ethnic differences. 1,19,21 he foramen ovale is an important fetal structure that closes after birth in most individuals and remains open as a patent foramen ovale (PFO) in approximately 25% of the healthy population. 1-3 In these individuals, bypass of the pulmonary circulation via shunting from the right-sided venous circulation to the left-sided arterial circulation is possible. Although most patients with PFOs are completely asymptomatic, reports from the late 1800 s by Cohnheim and Litten described cases of patients who were found to have the triad of deep venous thrombosis (DVT), PFO and systemic embolization. They hypothesized that the PFO enabled bypass of a venous thrombosis to the systemic arterial circulation, a process now termed paradoxical embolization. 4,5 Since those initial observations, additional studies have demonstrated a strong association between the presence of PFO and cryptogenic stroke in young patients. 6-11 In addition to its association with stroke, PFO has also been implicated in platypneaorthodeoxia, 12 decompression illness, 13 myocardial infarction, 14 obstructive sleep apnea, 15 and migraine headaches. 16 This review will focus on the relationship between PFO and stroke, discussing the embryology, epidemiology, association, mechanisms, diagnostic methods, associated anatomic factors and management strategies. EmbryologyThe right and left atria begin as a single chamber and separation b...

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“…apoC-III, encoded by the APOC3 gene, is a constituent of several apoB-containing lipoproteins, including chylomicrons, VLDL and LDL, and also HDL particles (30). Like apoC-I, apoC-III may inhibit LPL activity by preventing binding of LPL to the lipid-water interface of TG-rich lipoproteins and also by rendering LPL more susceptible to interference by ANGPTL4 (17).…”

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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Apolipoprotein C-III: From Pathophysiology to Pharmacology

Cited by 160 publications

References 111 publications

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

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

Patent Foramen Ovale and Stroke

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

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