Evolutionary conservation of drug action on lipoprotein metabolism-related targets

Abstract

Genetic analysis has shown that the slower than normal rhythmic defecation behavior of the clk-1 mutants of Caenorhabditis elegans is the result of altered lipoprotein metabolism. We show here that this phenotype can be suppressed by drugs that affect lipoprotein metabolism, including drugs that affect HMG-CoA reductase activity, reverse cholesterol transport, or HDL levels. These pharmacological effects are highly specific, as these drugs affect defecation only in clk-1 mutants and not in the wild-type and do not affect other behaviors of the mutants. Furthermore, drugs that affect processes not directly related to lipid metabolism show no or minimal activity. Based on these findings, we carried out a compound screen that identified 190 novel molecules that are active on clk-1 mutants, 15 of which also specifically decrease the secretion of apolipoprotein B (apoB) from HepG2 hepatoma cells. The other 175 compounds are potentially active on lipid-related processes that cannot be targeted in cell culture. One compound, CHGN005, was tested and found to be active at reducing apoB secretion in intestinal Caco-2 cells as well as in HepG2 cells. This compound was also tested in a mouse model of dyslipidemia and found to decrease plasma cholesterol and triglyceride levels.Thus, target processes for pharmacological intervention on lipoprotein synthesis, transport, and metabolism are conserved between nematodes and vertebrates, which allows the use of C. elegans for drug discovery.

Mitochondrial Oxidative Stress Alters a Pathway in Caenorhabditis elegans Strongly Resembling That of Bile Acid Biosynthesis and Secretion in Vertebrates

“…We have previously shown that the defecation cycle of clk-1 mutants, but not that of the wild type, is suppressed by lowering the levels of dietary cholesterol from 5 µg/ml to 2 µg/ml [23]. We have now extended this observation to the effect of high cholesterol (50 µg/ml), which has no effect on the wild type but further slows down the defecation of clk-1(qm30) mutants (Figure 3B).…”

“…Given the known function of MTP it was concluded that a type of MTP-dependent, LDL-like lipoprotein, distinct from yolk, affects the rate of defecation [14]. Reducing the level of dietary cholesterol mimics the effects of dsc-4 on the defecation cycle length of clk-1 mutants [15], [23]. These observations suggest that clk-1 mutants have slow defecation because they have high levels of LDL-like lipoproteins biosynthesis and secretion.…”

“…These observations suggest that clk-1 mutants have slow defecation because they have high levels of LDL-like lipoproteins biosynthesis and secretion. Furthermore, the MTP-dependent lipid transport system appears to be so well conserved between mammals and C. elegans that drugs that have been developed to lower lipid levels in humans can act as suppressors of the slow defecation rate of clk-1 [23]. In particular, the slow defecation is suppressed by drugs that antagonize high LDL levels by increasing HDL levels (e.g.…”

A single biochemical activity underlies the pleiotropy of the aging-related protein CLK-1

“…Animals were scored as adults after they had undergone the final molt and a vulva could be observed. Defecation cycle rates and pharyngeal pumping rate were measured as previously described 11, 46 .…”

The impact of mitochondrial oxidative stress on bile acid-like molecules inC. elegansprovides a new perspective on human metabolic diseases

“…Several observations suggest that dsc-4/mtp suppresses clk-1 by reducing the level of a type of MTP-dependent, LDL-like lipoprotein. For example, reducing the level of dietary cholesterol, which is a major constituent of lipoproteins whose reduction leads to reduce LDL levels in vertebrate, mimics the effects of dsc-4 on the slow germline development and the slow defecation cycle length of clk-1 mutants, 28 , 32 suggesting that those phenotypes of clk-1 mutants are due to high levels of LDL-like lipoproteins biosynthesis and secretion. It is not clear how elevated lipoprotein biosynthesis and secretion slow down the defecation cycle; however, the MTP-dependent lipid transport system appears to be so well conserved between mammals and C. elegans that drugs that have been developed to lower lipid levels in humans can act as suppressors of the slow defecation phenotype of clk-1 mutants 32 .…”