Antisense oligonucleotide reduction of apoB-ameliorated atherosclerosis in LDL receptor-deficient mice

Mullick, Adam E.; Fu, Wuxia; Graham, Mark; Lee, Richard G.; Witchell, Donna; Bell, Thomas A.; Whipple, Charles P.; Crooke, Rosanne M.

doi:10.1194/jlr.m011791

Cited by 43 publications

(31 citation statements)

References 36 publications

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“…The level of hepatic steatosis observed for ApoB siRNA treatment is consistent with our previous results ( 20 ). It is worth noting, however, that liver steatosis was not reported when antisense oligonucleotides (ASO) were used to knock down ApoB ( 26 ). Following ApoB ASO treatment, modest but not signifi cant increases in hepatic triglycerides were observed at week 6 that resolved by week 20 following biweekly administration ( 27 ).…”

Section: Dgat2 Silencing Attenuates Liver Steatosis Induced By Mtp Sisupporting

confidence: 79%

Rescue of Mtp siRNA-induced hepatic steatosis by DGAT2 siRNA silencing

Tep¹,

Mihaila²,

Freeman³

et al. 2012

Journal of Lipid Research

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Section: Dgat2 Silencing Attenuates Liver Steatosis Induced By Mtp Sisupporting

confidence: 79%

Rescue of Mtp siRNA-induced hepatic steatosis by DGAT2 siRNA silencing

Tep¹,

Mihaila²,

Freeman³

et al. 2012

Journal of Lipid Research

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“…Second-generation ASOs targeting murine apoB (ISIS 147764), whose pharmacology has been described in detail in two previous studies (11,12), or MTP (ISIS 144477), which in primary mouse hepatocytes reduced MTP mRNA NY), where MTP activity was quantitated as described previously (16).…”

Section: Resultsmentioning

confidence: 99%

“…In earlier publications from our laboratory (11,12), we suggested that antisense suppression of apoB does not result in hepatic steatosis due to secondary compensatory changes in the expression of multiple enzymes involved in lipogenic and ␤ -oxidative pathways in the liver. Data presented here confi rm and extend those observations.…”

Section: Discussionmentioning

confidence: 99%

“…Pharmacological suppression of hepatic apoB production via antisense oligonucleotide (ASO) treatment has also led to reductions in VLDL-C and LDL-C and the amelioration of atherosclerosis in murine preclinical models (11,12). Furthermore, although a murine-specifi c apoB ASO reduced apoB production and secretion from the liver, hepatic steatosis and elevation of transaminases were not observed in these mice (11).…”

Section: Mtp Activity Assaymentioning

confidence: 99%

“…In two previous publications ( 11,12 ), no reductions were observed in intestinal apoB48 protein levels; nor were there any effects on lipid absorption observed after extended administration of the apoB ASO in the DIO and LDLr Ϫ / Ϫ mice used in those experiments. However, in this most recent study, a modest but signifi cant reduction in apoB48 levels was noted.…”

Section: Analysis Of Hepatic Fatty Acid Synthesismentioning

confidence: 99%

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Comparison of the pharmacological profiles of murine antisense oligonucleotides targeting apolipoprotein B and microsomal triglyceride transfer protein

Lee

Graham

et al. 2013

Journal of Lipid Research

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This article is available online at http://www.jlr.org of elevated LDL-C levels and, ultimately, coronary heart disease are the statins (3). Although these drugs have proven to be potent and effi cacious, a signifi cant percentage of high-risk patients are unable to attain their ATP-III recommended LDL-C goals for several reasons, including ineffectiveness or intolerance to statins alone or in combination with other dyslipidemia agents (4, 5). These factors have led to a continued search for new drugs with unique mechanisms of action that lower plasma LDL-C levels.Two proteins involved in the formation of apoB-containing lipoprotein particles that have recently received considerable attention as potential therapeutic targets are apolipoprotein B (apoB) and microsomal triglyceride transfer protein (MTP) (6-8). Both are essential for the assembly and secretion of the apoB-containing lipoproteins (i.e., VLDL) synthesized in the liver and chylomicrons produced by enterocytes of the small intestine. In the liver, apoB100 is the main structural protein component of VLDL and LDL particles.Extensive biochemical studies indicate that apoB protein is primarily regulated at the post-transcriptional level (9). Initially, nascent apoB protein is transferred through the ER membrane and into the ER lumen. In the absence of suffi cient lipid or functional MTP, apoB fails to be lipidated and undergoes retrograde translocation into the cytosol, where it is ubiquitinated and degraded. However, in the presence of suffi cient lipid, apoB is lipidated in an MTP-dependent, two-step process, leading to the formation and secretion of a mature VLDL particle (10). VLDL then enters the circulation and is acted upon by lipolytic and lipid transfer enzymes that convert triglycerides TG-rich Abstract Therapeutic agents that suppress apolipoprotein B (apoB) and microsomal triglyceride transfer protein (MTP) levels/activity are being developed in the clinic to benefi t patients who are unable to reach target LDL-C levels with maximally tolerated lipid-lowering drugs. To compare and contrast the metabolic consequences of reducing these targets, murine-specifi c apoB or MTP antisense oligonucleotides (ASOs) were administered to chow-fed and high fatfed C57BL/6 or to chow-fed and Western diet-fed LDLr ؊ / ؊ mice for periods ranging from 2 to 12 weeks, and detailed analyses of various factors affecting fatty acid metabolism were performed. Administration of these drugs signifi cantly reduced target hepatic mRNA and protein, leading to similar reductions in hepatic VLDL/triglyceride secretion. MTP ASO treatment consistently led to increases in hepatic triglyceride accumulation and biomarkers of hepatotoxicity relative to apoB ASO due in part to enhanced expression of peroxisome proliferator activated receptor ␥ target genes and the inability to reduce hepatic fatty acid synthesis. Thus, although both drugs effectively lowered LDL-C levels in mice, the apoB ASO produced a more positive liver safety profi le.

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TSC22D4 is a molecular output of hepatic wasting metabolism

et al. 2013

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In mammals, proper storage and distribution of lipids in and between tissues is essential for the maintenance of energy homeostasis. Here, we show that tumour growth triggers hepatic metabolic dysfunction as part of the cancer cachectic phenotype, particularly by reduced hepatic very-low-density-lipoprotein (VLDL) secretion and hypobetalipoproteinemia. As a molecular cachexia output pathway, hepatic levels of the transcription factor transforming growth factor beta 1-stimulated clone (TSC) 22 D4 were increased in cancer cachexia. Mimicking high cachectic levels of TSC22D4 in healthy livers led to the inhibition of hepatic VLDL release and lipogenic genes, and diminished systemic VLDL levels under both normal and high fat dietary conditions. Liver-specific ablation of TSC22D4 triggered hypertriglyceridemia through the induction of hepatic VLDL secretion. Furthermore, hepatic TSC22D4 expression levels were correlated with the degree of body weight loss and VLDL hypo-secretion in cancer cachexia, and TSC22D4 deficiency rescued tumour cell-induced metabolic dysfunction in hepatocytes. Therefore, hepatic TSC22D4 activity may represent a molecular rationale for peripheral energy deprivation in subjects with metabolic wasting diseases, including cancer cachexia.

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Antisense oligonucleotide reduction of apoB-ameliorated atherosclerosis in LDL receptor-deficient mice

Cited by 43 publications

References 36 publications

Rescue of Mtp siRNA-induced hepatic steatosis by DGAT2 siRNA silencing

Rescue of Mtp siRNA-induced hepatic steatosis by DGAT2 siRNA silencing

Comparison of the pharmacological profiles of murine antisense oligonucleotides targeting apolipoprotein B and microsomal triglyceride transfer protein

TSC22D4 is a molecular output of hepatic wasting metabolism

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