Cholesterol metabolism and aging

Kreisberg, Robert A.; Kasim, Sidika E.

doi:10.1016/0002-9343(87)90272-5

Cited by 134 publications

(96 citation statements)

References 24 publications

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“…In humans, reductions in the rate of whole-body nitric oxide production correlate strongly with increased circulating LDL-cholesterol in age-matched individuals ( 49 ). Whole-body nitric oxide production also decreases with age ( 50,51 ), coincident with a decrease in LDL clearance rates ( 52,53 ). The ability of lipoproteins to inhibit eNOS activity ( 54,55 ) likely explains part of the correlation between LDL-cholesterol and nitric oxide production; however, the correlation is much stronger in individuals with two normal LDLR alleles than in individuals with a defective LDLR allele ( 49,56 ), suggesting that nitric oxide also promotes LDLR function.…”

Section: Discussionmentioning

confidence: 99%

S-nitrosylation of ARH is required for LDL uptake by the LDL receptor

Zhao

Pompey

Dong

et al. 2013

Journal of Lipid Research

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This article is available online at http://www.jlr.org (ARH) and the disabled-like protein 2 (dab2). Both ARH and dab2 target LDLRs to coated pits through binding sites for the LDLR, clathrin, and the adaptor protein 2 (AP-2) complex. ARH binds to the FDNPVY 807 sequence of the LDLR through a phosphotyrosine-binding (PTB) domain, to the heavy chain of clathrin through a clathrin box sequence, and to the ␤ 2-subunit of AP-2 through a sequence with strong homology to the AP-2-binding sequences of ␤ -arrestins ( 5-8 ) ( Fig. 1A ). Y807 of the FDNPVY 807 plays a critical role in the interaction of ARH and dab2 with the LDLR, and mutation of Y807 to either cysteine or alanine cripples LDLR-dependent LDL uptake ( 3,5,8,9 ). By contrast, uptake of VLDL remnants does not require ARH, dab2, or a functional FDNPVY sequence because binding of VLDL remnants to the LDLR induces a separate endocytic process that involves a second internalization motif on the LDLR cytoplasmic domain ( 10 ). It is not clear why the LDLR needs an induced process for VLDL remnant uptake when the FDNPVY-dependent process can internalize both LDL and VLDL remnants, nor why the FDNPVY process utilizes both the ARH and dab2 adaptors when either adaptor is suffi cient to support lipoprotein uptake by the LDLR.A key question is why an ARH is necessary. ARH has highest expression in kidney, liver, and placenta ( 11 ); however, dab2 is also highly expressed in both kidney and placenta, and it is dab2, not ARH, that is required for normal placental and kidney function ( 12 ). Hepatocytes and peripheral blood leukocytes lack dab2 ( 13,14 ), and ARH defi ciency in both humans and mice sharply reduces LDL clearance rates, resulting in hypercholesterolemia ( 15-18 ). Why hepatocytes and leukocytes normally rely upon ARH is unclear because both cell types lose their dependence on ARH for LDL uptake when dab2 expression is induced Abstract The LDL receptor (LDLR) relies upon endocytic adaptor proteins for internalization of lipoproteins. The results of this study show that the LDLR adaptor autosomal recessive hypercholesterolemia protein (ARH) requires nitric oxide to support LDL uptake. Nitric oxide nitrosylates ARH at C199 and C286, and these posttranslational modifi cations are necessary for association of ARH with the adaptor protein 2 (AP-2) component of clathrin-coated pits. In the absence of nitrosylation, ARH is unable to target LDL-LDLR complexes to coated pits, resulting in poor LDL uptake. The role of nitric oxide on LDLR function is specifi c for ARH because inhibition of nitric oxide synthase activity impairs ARH-supported LDL uptake but has no effect on other LDLR-dependent lipoprotein uptake processes, including VLDL remnant uptake and dab2-supported LDL uptake. These fi ndings suggest that cells that depend upon ARH for LDL uptake can control which lipoproteins are internalized by their LDLRs through changes in nitric oxide. -Zhao, Z., S. Pompey, H. Dong, J. Weng, R. Garuti, and P. Michaely. The LDL receptor (LDLR) internalizes a broad spectrum ...

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Section: Discussionmentioning

confidence: 99%

S-nitrosylation of ARH is required for LDL uptake by the LDL receptor

Zhao

Pompey

Dong

et al. 2013

Journal of Lipid Research

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“…HDL concentrations decrease in males during puberty and early adulthood, and thereafter remain lower than those in women. 7 HDL cholesterol in adults was shown to decrease with age in both men and women in prospective studies. 8,9 The most striking decreases, most likely attributable to hormonal changes, were observed in postmenopausal women.…”

Section: Hdl Cholesterol Levels Into Old Agementioning

confidence: 95%

Interrelationships Among HDL Metabolism, Aging, and Atherosclerosis

Walter

2009

ATVB

105

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Abstract-HDL plasma concentrations decline with age in prospective studies. Decline in HDL concentration and function may occur secondary because of hormonal changes, inflammatory processes, and diabetes mellitus. Beyond these effects specific aging processes may be involved. Replicative aging, the telomere-driven loss of divisional capacity, is a species-specific aging mechanism that may decrease HDL concentration and function. Cross-sectionally, by contrast, HDL levels do not change much or even slightly increase with age, suggesting that only people with still high HDL concentrations survive. A selection bias by HDL lowering genetic variation may explain why HDL deficiency is extremely rare among centenarians. Vice versa, HDL may modulate the aging process, not only by its well-known antiatherogenic effects, eg, its ability to remove cellular lipids and by antiatherogenic pleiotropic effects on cell survival, but possibly also by direct interfering with aging signaling or survival factor KLOTHO. Most of the current findings, however, are based on cell culture and selected animal experiments and await further confirmation by appropriate in vivo models. T he influence of age on atherosclerosis is generally explained by the simple passage of time and a higher number and severity of risk factors with increasing age. However, the observation of senescence-like changes in atherosclerotic lesions, 1 the severe atherosclerosis in premature aging syndromes, 2 and the identification of age as by far the most predictive independent risk factor for atherosclerosis effective even in absence of other risk factors 3 suggests that atherogenesis is more directly related to the aging process than previously presumed.Aging is a complex process that (on the cellular level) includes cell cycle arrest, morphology remodeling with functional decline, chromatin silencing with profound gene expression changes, and changes in metabolism. As summarized in Figure 1, different triggers may act together in a cooperative fashion and use overlapping signaling pathways to induce and propagate the aging process. 4 Replicative aging results from the progressive shortening of telomeres (composed of conserved nucleotide sequences, TTAGGG in vertebrates) attributable to incomplete end replication during cell divisions. It may protect against increased cancer risk but may also contribute to atherosclerosis in later life, particularly at "atherosclerosis-prone areas" with high replication rates. 5 Next to age, a low high-density lipoprotein (HDL) cholesterol level is one of the strongest predictors of premature coronary heart disease and stroke. 6 In contrast to high low-density lipoprotein (LDL) cholesterol, low HDL cholesterol remains a powerful risk predictor into old age. HDL may directly influence specific aging processes and, vice versa, aging may influence HDL concentration and function. However, it is important to bear in mind the caveats of the current studies. First, most findings are based on cell culture and animal models and have not be...

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“…In women LDL-C plateaus on average 10 years later than in men. 4 After the age of 60 years, mean LDL-C is higher in women than in men, with menopausal hormonal changes contributing to the higher LDL-C observed in women. Mechanistically LDL-C rises in older individuals because of a decreased LDL-C fractional catabolic rate, which is likely secondary to decreased hepatic LDL receptor expression.…”

Section: Age-related Changes In Lipoprotein Metabolismmentioning

confidence: 99%

Statin therapy for the octogenarian?

Blom

2012

Journal of Endocrinology, Metabolism and Diabetes of South Afri

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Cardiovascular risk increases progressively with age. Statins in octogenarians may therefore potentially bring about large reductions in absolute risk. Epidemiological studies, however, show that statin prescription declines with age and is lowest in the oldest patients with the highest cardiovascular risk. Reasons for low statin utilisation in the elderly include safety concerns, doubts about the utility of statin therapy in those of advanced age and a paucity of definite trial evidence supporting statin prescription in octogenarians. Some of the more recently completed statin outcome trials have randomised patients as old as 82 years. A meta-analysis of secondary prevention, with patients aged 65-82 years at randomisation, supported statin prescription in this age group, as statin therapy was associated with relative risk reduction similar to that observed in younger patients. A Swedish registry study showed improved survival in octogenarians prescribed a statin following hospitalisation with an acute myocardial infarction. Currently there is no definite evidence that statin therapy prevents or ameliorates cognitive impairment or dementia. Statin therapy should be considered in octogenarians at high cardiovascular risk, taking into account factors such as biological vs. chronological age, life expectancy, quality of life, risk of interaction with medications taken for co-morbidities and the ability of the patient to take the statin safely.Peer reviewed.

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Cholesterol metabolism and aging

Cited by 134 publications

References 24 publications

S-nitrosylation of ARH is required for LDL uptake by the LDL receptor

S-nitrosylation of ARH is required for LDL uptake by the LDL receptor

Interrelationships Among HDL Metabolism, Aging, and Atherosclerosis

Statin therapy for the octogenarian?

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