高密度脂蛋白胆固醇偏高怎么回事

高密度脂蛋白胆固醇偏高怎么回事

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      Conditions that cause high HDL-C levels

      Genetic conditions associated with elevated HDL-C levels,are also described as primary familial or secondary hyperalphalipoproteinemia (HALP) due to the elevated Apo-AI and Apo-AII levels observed in these conditions.

      Patients with HALP tend to be asymptomatic,aside from some rare reported cases of juvenile or premature corneal opacities or multiple symmetric lipomatosis,and are characterized by high levels of HDL-C and low incidence of CVD.

      Due to its lack of clinical symptoms,patients are usually identified through the routine assessment of a lipid profile or may have history of a relative found with elevated HDL-C levels. No treatment is generally required.

      In this review we will only describe the primary familial causes of HALP.

      # Primary familial HALP

      Primary familial HALP is defined as HDL-C levels greater than the 90th percentile for age and gender,a history of relatives with high HDL-C,and the absence of secondary causes of increased HDL-C levels,such as medications,malignancies,or liver disease. This condition is thought to coexist with longevity and to provide some type of protection from atherosclerotic disease. Primary familial HALP is an autosomal-dominant condition and may result from genetic mutations of ApoA-I,causing overproduction,or from certain variants of apolipoprotein C-III (ApoC-III). It is diagnosed incidentally with plasma HDL-C levels above 80 mg/dL.

      # Selective upregulation of ApoA-I

      ApoA-I is the major protein of HDL. It acts as a structural protein,mediates RCT,and activates LCAT.

      In addition to its function in the HDL-C metabolism,this apolipoprotein also has anti-inflammatory properties,which may contribute to its cardioprotective role.

      The selective upregulation of ApoA-I results in ApoA-I overproduction. It is characterized by elevated HDL-C and ApoA-I levels and has been linked to a reduced risk of CVD.

      # ApoC-III variants

      ApoC-III is a small apolipoprotein,which is synthesized mainly in the liver,is carried in the circulation by VLDL and HDL,and regulates plasma TG homeostasis. This apolipoprotein impairs the hydrolysis of triglyceride-rich lipoproteins (TRL) by inhibiting the activity of the lipoprotein lipase (LPL) and delaying the hepatic uptake of TRL by remnant receptors,thus resulting in elevated plasma TG levels.,Beyond its role on TG metabolism,ApoC-III has been also associated with increased risk of CVD. It promotes HDL dysfunction,facilitates the interaction of monocytes and endothelial cells,stimulates smooth muscle cell proliferation,and alters platelet activity,thus promoting atherosclerosis.

      Furthermore,plasma ApoC-III concentration is directly related with the plasma TG concentration. Therefore,mutations that interrupt ApoC-III function or loss-of-function ApoC-III mutations are associated with very low plasma TG levels and elevated HDL-C levels,resulting in a reduction of the risk for CVD.

      Studies have described that carriers of ApoC-III loss-of-function mutations have up to 39% lower plasma TG levels,22% higher plasma HDL-C levels,and 16% lower plasma LDL-C levels. Of note,carriers of ApoC-III loss-of-function mutations enjoy a 40% lower risk of coronary heart disease (CHD),as compared to non-carriers.

      # CETP deficiency

      CETP mediates the exchange of CE for TG between HDL and VLDL/LDL and regulates the lipid composition and particle size of lipoproteins. CETP activity correlates directly with LDL-C concentration and inversely with HDL-C concentration.

      CETP deficiency is an autosomal recessive inherited metabolic disorder,which was first studied in Japan in the 1980s. It is considered one of the most important and frequent causes of HALP in the Japanese population.,Two common mutations in the CETP gene have been described particularly in the Japanese population: intron 14 splicing defect (In14),a null mutation with strong effects on plasma CETP activity and levels and HDL-C levels,and a missense mutation in exon 15 (Ex15) with less pronounced effects on plasma HDL-C levels compared to In14. Other less common mutations described are the intron 10 splicing defect (In10) and the exon 6 nonsense mutation (Ex6).

      The loss-of-function CETP enzyme results in elevated levels of ApoA-I and ApoA-II due to decreased turnover,significantly elevated HDL-C levels in homozygotes (usually >100 mg/dL),and moderately elevated HDL-C levels in heterozygotes due to lack of HDL remodeling. Thus,the HDL particles in this condition are enriched with CE and apolipoprotein E (ApoE) and have a low TG content. Moreover,there is increased hydrolysis of LDL leading to decreased LDL-C levels.,Even though CETP deficiency is associated with elevated HDL-C and decreased LDL-C,its antiatherogenic potential remains very controversial with some studies suggesting a decreased risk for CVD in such patients and others indicating that,despite their high HDL-C content,these particles have a decreased capacity for cholesterol efflux and may not have antiatherogenic properties.,Several studies were conducted with CETP inhibitors,but their effects on CVD risk were detrimental,neutral,or at most slightly positive,despite a substantial increase in HDL-C levels. Only anacetrapib produced a small decrease in the risk for CVD when added to statin therapy; however,this was achieved mainly by decreasing the non-HDL-C,rather than by increasing the HDL-C. However,more studies are needed to definitely determine the therapeutic potential of CETP inhibitors in the treatment of CVD.

      # Scavenger receptor class B type I (SR-BI) mutations

      SR-BI,encoded by the SCARB1 gene, is a main component of the RCT pathway with high affinity for HDL-C. It mediates the selective uptake of CE from HDL-C in liver and steroidogenic tissues and facilitates the secretion of cholesterol into bile. SR-BI is expressed in the liver and in macrophages in atherosclerotic plaques.,Furthermore,SR-BI are multi-ligand receptors binding other lipoproteins,such as LDL and VLDL.

      Certain mutations in the SR-BI gene have been described and among them is exon 8 rs5888 single nucleotide polymorphism (SNP),associated with a decreased SR-BI protein expression and function,resulting in altered lipid levels in humans. Another mutation described in the SR-BI gene is a missense mutation,in which leucine replaces proline at position 376 (P376L). This mutation impairs posttranslational processing of SR-BI and results in almost complete loss of its function and dysregulation of the selective HDL-C uptake in transfected cells.

      The decreased activity or loss of SR-BI function results in decreased HDL-C bile secretion,leading to elevated HDL-C levels. However,despite the high plasma HDL-C concentration observed in this condition,carriers exhibit increased risk of CVD due to impaired RCT pathway caused by the reduced hepatic SR-BI function.,More specifically,carriers of the P376L mutation (described above) have been shown to have a 79% higher risk of CHD,as compared to non-carriers.

      SR-BI mutations may also be associated with an increased risk for adrenal glucocorticoid insufficiency and impaired platelet function.,Endothelial lipase (EL) is a member of the triacylglycerol (TAG) lipase gene family,along with LPL,hepatic lipase,and pancreatic lipase. Interestingly,it is the only identified lipase that is synthesized and expressed by endothelial cells.

      It promotes HDL particle binding and uptake,in addition to the selective uptake of HDL-CE due to its phospholipase activity. EL also cleaves HDL-phospholipids resulting in the release of fatty acids and lysophospholipids,which are then taken up by the cells expressing this enzyme.

      By decreasing the triglyceride and phospholipid content of HDL,EL is a strong negative regulator of plasma HDL-C levels,and thus EL loss-of-function mutations lead to increased HDL-C levels. Notwithstanding,the cardiovascular connotations of EL loss-of-function mutations are still unclear with some studies describing some cardioprotective properties,whereas others do not show any associated reduction in the risk of CHD.

      Although rare in the overall population,primary extremely low HDL-C levels result from monogenic disorders,such as ApoA-I deficiency,several ApoA-I missense mutations (such as ApoA-I Milano,ApoA-I Paris and others),Tangier disease,LCAT deficiency,or ABCA1 deficiency. Aside from certain ApoA-I missense mutations (including ApoA-I Milano and ApoA-I Paris),these conditions are associated with premature CVD due to abnormal accumulation of cholesterol.

      The early evaluation to assess the risk for atherosclerotic disease,as well as to rule out any secondary causes,plays a major role in the care for these patients. The high risk for CVD warrants comprehensive secondary prevention measures. These include achieving an LDL-C 200 mg/dL). Affected individuals present with enlarged yellow-orange tonsils,thrombocytopenia,peripheral neuropathy (approximately 50% are affected),and hepatosplenomegaly due to ectopic deposition of cholesterol-laden macrophages in these tissues.,Homozygous and compound heterozygous carriers of the disease who are more than 30 years of age have a six-fold higher risk of CVD,whereas heterozygotes exhibit a greater than three-fold increase in the frequency of coronary artery disease (CAD).

      To date,aside from the symptomatic management,no treatment has been found to prevent the progression of this disease,as drugs commonly used to increase the HDL-C have proven to be ineffective in these individuals. Patients should be encouraged to avoid any lifestyle habit that can promote further progression of atherogenesis.","department":"