Antisense oligonucleotide reduction of DGAT2 expression improves hepatic steatosis and hyperlipidemia in obese mice

Yu, Xing; Murray, Susan F.; Pandey, Sanjay; Booten, Sheri; Bao, Dingjiu; Song, Xiuzhen; Kelly, Susan; Chen, Songyuan; McKay, Robert A.; Monia, Brett P.; Bhanot, Sanjay

doi:10.1002/hep.20783

Cited by 254 publications

(236 citation statements)

References 37 publications

(37 reference statements)

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“…Thus, targeting of hepatic FATPs may be preferable over downstream targets in lipid metabolism such as DGAT2. Indeed, although suppression of hepatic DGAT2 via antisense oligonucleotides led to reduced hepatosteatosis in obese mice, it neither improved insulin sensitivity nor body weight (19), and hepatic DGAT overexpression resulted in steatosis but not insulin resistance (30). This is in clear contrast to our findings here for FATP5 knockdown, which leads to a reversal of obesity-induced NAFLD and improves whole-body glucose homeostasis.…”

Section: Discussioncontrasting

confidence: 99%

“…A single injection of sdsAAV-shRNA viruses sufficed to suppress expression of FATP5, resulting in phenotypes that were largely comparable with those of classical knock-out models while being substantially less timeand work-consuming. Further, major advantages of AAV-mediated gene knockdown over previously reported methods aiming at gene hypomorphism, such as antisense oligonucleotide injections (19), different double-stranded small RNA injections (20), or other viral approaches (e.g. adenoviral (21) or retroviral (22)), include robust and liver-directed transduction, lack of inherent pathogenicity, and potential for long term persistence of shRNA expression (11).…”

Section: Discussionmentioning

confidence: 99%

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Silencing of Hepatic Fatty Acid Transporter Protein 5 in Vivo Reverses Diet-induced Non-alcoholic Fatty Liver Disease and Improves Hyperglycemia

Doege

Grimm

Falcon

et al. 2008

Journal of Biological Chemistry

136

103

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Non-alcoholic fatty liver disease is a serious health problem linked to obesity and type 2 diabetes. To investigate the biological outcome and therapeutic potential of hepatic fatty acid uptake inhibition, we utilized an adeno-associated virus-mediated RNA interference technique to knock down the expression of hepatic fatty acid transport protein 5 in vivo prior to or after establishing non-alcoholic fatty liver disease in mice. Using this approach, we demonstrate here the ability to achieve specific, non-toxic, and persistent knockdown of fatty acid transport protein 5 in mouse livers from a single adeno-associated virus injection, resulting in a marked reduction of hepatic dietary fatty acid uptake, reduced caloric uptake, and concomitant protection from diet-induced non-alcoholic fatty liver disease. Importantly, knockdown of fatty acid transport protein 5 was also able to reverse already established non-alcoholic fatty liver disease, resulting in significantly improved whole-body glucose homeostasis. Thus, continued activity of hepatic fatty acid transport protein 5 is required to sustain caloric uptake and fatty acid flux into the liver during high fat feeding and may present a novel avenue for the treatment of non-alcoholic fatty liver disease.The worldwide prevalence of non-alcoholic fatty liver disease (NAFLD) 2 is presently estimated at 30% of the general population and affects a majority of patients with obesity and type 2 diabetes (1, 2). In obese individuals, chronically elevated serum free fatty acids (FFAs) and high insulin levels lead to both increased FFA uptake by the liver and increased synthesis of lipids, resulting in hepatic triglycerides (TG) accumulation, typically accompanied by hepatic insulin desensitization (1, 3) involving protein kinase C ⑀ (3). Current pharmacological treatment strategies for NAFLD focus principally on increasing hepatic fatty acid oxidation (4) and improving extrahepatic insulin sensitivity (5). However, none of these treatment methods reduce hepatic uptake of dietary fats, and novel therapeutics that specifically aim at reversing NAFLD in the context of obesity would be highly desirable.Based on the premises that obesity-associated NAFLD is primarily driven by the continuous protein-mediated uptake of fatty acids by the liver and that NAFLD is a contributing factor to whole-body insulin desensitization, we argued that blocking proteins responsible for hepatic fatty acid uptake should prevent or reverse hepatic steatosis, thus improving insulin sensitivity and glucose homeostasis. Two members of the fatty acid transport protein (FATP) family, FATP2 and FATP5, are robustly expressed in liver (6) and are thought to be involved in the early steps of long-chain fatty acid uptake/activation (7,8). We recently demonstrated the importance of FATP5 in hepatic lipid metabolism by showing that deletion of FATP5 partially protected mice from developing high fat diet-induced obesity and improved insulin-sensitivity (9, 10).To explore the consequences of hepatic FATP5 ablation ...

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Silencing of Hepatic Fatty Acid Transporter Protein 5 in Vivo Reverses Diet-induced Non-alcoholic Fatty Liver Disease and Improves Hyperglycemia

Doege

Grimm

Falcon

et al. 2008

Journal of Biological Chemistry

136

103

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“…Fat makes the liver vulnerable to endotoxins and ischemic reperfusion damage, impairs liver regeneration (Uesugi et al, 2001) and causes hepatic insulin resistance (Kim et al, 2001). Acyl-CoA: diacylglycerol acyltransferase 2 (DGAT2) is the final step and rate limiting reaction in triglyceride synthesis (Choi et al, 2007;Yu et al, 2005;Wang et al, 2010). Reactive oxygen species (ROS) together with tumor necrosis factor (TNF) α and monocyte chemoattractant protein (MCP) -1 represent the "second hit" (Jou et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Hepatoprotective effect of tamoxifen on steatosis and non-alcoholic steatohepatitis in mouse models

et al. 2012

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-Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid accumulation that starts with steatosis and progresses to non-alcoholic steatohepatitis (NASH). Recently, the number of patients with such liver diseases has increased, but the understanding of the fundamental mechanisms and appropriate therapies are lacking. Tamoxifen (TAM) is a selective estrogen receptor modulator. We previously reported that TAM plays a protective role against drug-induced and chemical-induced acute liver injuries. However, the effects of TAM on chronic liver injury, including steatosis and NASH, remain to be addressed. We first found that the administration of TAM to mouse models of steatosis and NASH significantly decreased the plasma ALT and AST levels. The administration of TAM decreased the accumulated fat and inflammation in the livers in both mouse models. In addition, we observed decreased hepatic mRNA levels of triglyceride synthesis, acyl-CoA: diacylglycerol acyltransferase 2 (DGAT2), proinflammatory cytokines, tumor necrosis factor (TNF) α, and chemokines, monocyte chemoattractant protein (MCP) -1. TAM increased the extracellular signal-regulated kinase (ERK) phosphorylation, which is related to the proliferation and regeneration of liver and to decreased DGAT2 gene expression. Furthermore, a decrease in eukaryotic translational initiation factor (eIF2α), which is involved in apoptosis, was observed in both models. These findings suggest that TAM treatment exerts a hepatoprotective effect against steatosis and NASH, presumably via up-regulation of the ERK pathways and attenuation of eIF2α activation. These pathways represent a potential therapeutic target for steatosis and NASH in drug development.

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“…Third, the knockout (KO) of Acc2 (also known as Acacb) resulted in increased energy expenditure as measured by the volume of oxygen consumed Á V O 2 [7,8]. It has also been shown that inhibition of the downstream genes Scd1 and Dgat2 also lowers Acc1 (also known as Acaca) and Acc2 expression by a feedback mechanism [9][10][11]. These results supported drug research targeted approaches to lower malonyl-CoA.…”

Section: The Premisementioning

confidence: 72%

Targeting energy expenditure via fuel switching and beyond

Geisler

2010

Diabetologia

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Since over-nutrition accelerates the development of obesity, progression to type 2 diabetes, and the associated co-morbidity and mortality, there has been a keen interest in therapeutic interventions targeting mechanisms that may curb appetite, increase energy expenditure or at least attenuate insulin resistance. Over the past decade, numerous peri-mitochondrial targets in the de novo lipid synthesis pathway have been linked to an increase in energy expenditure and the drug development industry has pursued the gene products involved as candidates to develop drugs against. The basis of this link, and specifically the premise that lowering tissue and cellular malonyl-CoA can increase energy expenditure, is scrutinised here. The argument presented is that fuel switching as effected by changes in cellular malonyl-CoA concentrations will not trigger the mitochondria to increase energy expenditure because: (1) an increase in beta-oxidation by lowering respiratory exchange ratio (indicative of the metabolic fuel consumed) does not equal an increase in energy expenditure (how rapidly fuel is consumed); (2) the ATP:oxygen ratios (i.e. ATP energy made:oxygen required for the reaction) are similar when metabolising lipids (2.8) vs glucose (3.0); (3) substrate availability (NEFA) does not drive energy expenditure in vivo; and (4) the availability of ADP in the mitochondrial matrix determines the rate of energy expenditure, not the availability of fuel to enter the mitochondrial matrix. To increase mitochondrial energy expenditure, work must be done (exercise) and/or the mitochondrial proton leak must be enhanced, both of which increase availability of ADP. In fact, despite the historic taboo of chemical uncoupling, this mechanism validated in humans is closest on task to increasing whole-body energy expenditure. Chemical uncoupling mimics the naturally occurring phenomenon of proton leak, accelerating the metabolism of glucose and lipids. However, it is completely non-genomic (i.e. the target is a location, not a gene product) and is not associated with addiction or mood alterations common to satiety agents. A significant hurdle for drug development is to discover a safe mitochondrial uncoupler and to formulate it potentially as a pro-drug and/or oral pump, to avoid the issue of overdosing experienced in the 1930s. The potential therapeutic impact of such a compound for an overnutritioned patient population could be profound. If effective, the mitochondrial uncoupler mechanism could resolve many of the associated diseases such as type 2 diabetes, hypertension, obesity, depression, sleep apnoea, non-alcoholic steatohepatitis, insulin resistance and hyperlipidaemia, therefore becoming a 'disease-modifying therapy'.

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Antisense oligonucleotide reduction of DGAT2 expression improves hepatic steatosis and hyperlipidemia in obese mice

Cited by 254 publications

References 37 publications

Silencing of Hepatic Fatty Acid Transporter Protein 5 in Vivo Reverses Diet-induced Non-alcoholic Fatty Liver Disease and Improves Hyperglycemia

Silencing of Hepatic Fatty Acid Transporter Protein 5 in Vivo Reverses Diet-induced Non-alcoholic Fatty Liver Disease and Improves Hyperglycemia

Hepatoprotective effect of tamoxifen on steatosis and non-alcoholic steatohepatitis in mouse models

Targeting energy expenditure via fuel switching and beyond

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