Research on the molecular basis of dyslipidemia has increasingly lateralized from cholesterol metabolism to a broader landscape reflecting the highly regulated integration of substrate generation and utilization of lipids and carbohydrates, and their relationship to vascular disease. The contemporary appreciation of the relationship of insulin resistance and triglyceride-based atherogenesis to cardiac disease leads to examination of new therapeutic targets, some of which are presented here.
Adenosine monophosphate kinase (AMPK) occupies a central role in regulation of both lipid and carbohydrate metabolism. It acts through a number of transcriptional events, effecting a shift from lipogenesis and gluconeogenesis to fatty acid oxidation and reduced glucose production. sterol regulatory element-binding protein (SREBP)-mediated fatty acid synthesis is inhibited, whereas oxidation of fatty acids by mitochondria is increased. Gluconeogenesis is decreased transcriptionally at the level of phosphoenol pyruvate carboxykinase and glucose-6-phosphatase. An additional effect that could mitigate atherosclerosis is suppression of inflammation, associated with reduction of C-reactive protein levels. A single small molecule has been identified that increases the activity of AMP kinase while inhibiting ATP citrate lyase. The latter inhibits the synthesis of fatty acids and cholesterol [1â–ª]. Clinical trials with this compound have demonstrated decreases in LDL levels of 26% in nondiabetic individuals and over 40% in diabetic individuals [2 â–ª ,3,4][2 â–ª ,3,4][2 â–ª ,3,4].
The central roles of the SREBP proteins in the regulation of both fatty acid and cholesterol synthesis present potential points of regulation. SREBP-1a and 1b are involved in fatty acid synthesis, whereas SREBP-2 is a key activator of cholesterol biosynthesis. Inhibition of these mediators holds promise of regulation of these critical processes [5â–ª].
One of the small apolipoproteins, apoC-III, inhibits lipoprotein lipase-mediated hydrolysis of triglycerides in circulating VLDLs and chylomicrons, and inhibits the hepatic uptake of remnant lipoproteins. It also decreases hydrolysis of triglycerides by hepatic lipase [6]. This activity may have evolved to maintain a sufficient level of triglyceride-rich lipoproteins to provide for sequestration of endotoxins emanating from gram-negative bacteria. The level of apoC-III in plasma is positively associated with risk of atherosclerosis, and genetic deficiency is cardioprotective. In addition to risk of coronary disease associated with hypertriglyceridemia, there is a strong association of acute pancreatitis with triglyceride levels, beginning around 1000 mg/dl. Thus, there are two expected benefits of reducing apoC-III. A recent trial of an antisense oligonucleotide directed against the mRNA for this protein in individuals with triglycerides of 350–2000 mg/dl resulted in reductions of triglycerides of nearly 80%. In individuals also receiving fibrates, the results were similar [7▪▪].
Cholestryl ester storage disease, estimated to be present in homozygous form in about 9000 Americans, results from genetically impaired lysosomal acid lipase. Cholesteryl esters accumulate in hepatic lysosomes. Hypercholesterolemia often mimics familial hypercholesterolemia, and low levels of HDL cholesterol frequently occur. Hepatomegaly is caused by microvesicular steatosis that frequently progresses to liver failure. The hypercholesterolemia can lead to arteriosclerotic heart disease. Statin treatment lowers circulating LDL but increases the hepatic uptake of cholesteryl esters, an activity expected to exacerbate the steatosis. Preliminary studies of recombinant lysosomal acid lipase have demonstrated normalization of transaminases and, over the course of 52 weeks, a 60% reduction in LDL cholesterol, a 9% increase in HDL cholesterol, and a significant reduction in circulating triglycerides [8â–ª]. Paradoxically, the plasma LDL level rises initially with treatment, presumably reflecting the temporary downregulation of hepatic LDL receptors from the release of unesterified cholesterol by the lipase. This disorder may be present with other genetic hypercholesterolemias, compounding the clinical phenotype.
Acknowledgements
None.
Financial support and sponsorship
J.P.K. and M.J.M. are recipients of support from the Joseph Drown and Campini Foundations.
Conflicts of interest
J.P.K. is a recipient of research funding from Synageva, Inc.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- â–ª of special interest
- ▪▪ of outstanding interest
REFERENCES
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A small molecule, fatostatin has been identified which blocks the translocation of SRBP from the endoplasmic reticulum to the Golgi apparatus with resultant reduction in body fat stores, glucose levels, and hepatic triglyceride content.
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Clinical demonstration of the utility of antisense apoC-III in hypertriglyceridemia, an important risk factor for coronary disease and pancreatitis.
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Demonstration of the effect of recombinant lysosomal acid lipase in individuals with cholesteryl ester storage disease, perhaps an underdiagnosed disorder.
