Reversal of Hypertriglyceridemia, Fatty Liver Disease, and Insulin Resistance by a Liver-Targeted Mitochondrial Uncoupler

Perry, Rachel J.; Kim, Tae-Han; Zhang, Xian‐Man; Lee, Hui Young; Pesta, Dominik; Popov, Violeta; Zhang, Dongyan; Rahimi, Yasmeen; Jurczak, Michael J.; Cline, Gary W.; Spiegel, David A.; Shulman, Gerald I.

doi:10.1016/j.cmet.2013.10.004

Cited by 194 publications

(194 citation statements)

References 23 publications

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“…Inhibiting lipolysis with an ATGL inhibitor lowered rates of hepatic gluconeogenesis in normal chow-fed rats, insulin-resistant high-fat-fed rats, and insulin-resistant rats treated with an antisense oligonucleotide to knock down hepatic and adipocyte IRTK. The importance of intrahepatic DAG and acetyl-CoA in promoting hepatic insulin resistance and increased hepatic gluconeogenesis was also demonstrated in rats treated with either a liver-targeted or controlled release formulation of a mitochondrial protonophore (81,118). In both cases, subtle increases in hepatic mitochondrial inefficiency reduced hepatic DAG and acetyl-CoA content with marked improvement in hepatic insulin signaling and reductions in rates of hepatic gluconeogenesis and fasting hyperglycemia in diabetic animals.…”

Section: Discussionmentioning

confidence: 88%

“…However, a disassociation between ceramide content and tissue insulin resistance has been reported in multiple studies (70,71,81), and the underlying mechanism linking ceramides to insulin resistance has not been fully resolved. Recently, two studies examined how a specific ceramide species, C16:0, impedes mitochondrial function, allowing triglyceride accumulation and insulin resistance (82,83).…”

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confidence: 99%

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The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux

Samuel¹,

Shulman²

2016

Journal of Clinical Investigation

967

819

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In most natural habitats, calorie availability is scarce and unpredictable, necessitating the evolution of systems for the efficient storage and utilization of energy. But in our modern, mechanized society, caloric demands are minimized, while highly palatable, calorie-dense foods and beverages are readily available. These changes have fostered the current pandemic of obesity and comorbid conditions of nonalcoholic fatty liver disease (NAFLD), atherosclerosis, and type 2 diabetes (T2D). Insulin resistance is a common feature of all these diseases, and much effort has been invested in delineating the pathogenesis of insulin resistance. We will first review the role of insulin and nutrients (specifically glucose and fatty acids) in nutrient storage ( Figure 1) and then use this framework to explore the various defects that give rise to insulin resistance and T2D (Figure 2). Postprandial hepatic glucose and lipid metabolismThe simple act of eating rapidly shifts hepatic glucose metabolism from glucose production to glucose storage, a complex transition regulated by multiple factors including nutrients, alterations in pancreatic and enteric hormones, and neural regulation. Insulin is a crucial regulator of this transition, primarily by activating glycogen synthase (1). The importance of insulin is seen in patients with type 1 diabetes (T1D), who only synthesize one-third the amount of hepatic glycogen as control subjects after a mixed meal (2). Yet, hyperinsulinemia, in the absence of hyperglycemia, promotes hepatic glycogen cycling with minimal net hepatic glycogen synthesis (1). And hyperglycemia, without hyperinsulinemia, inhibits hepatic glycogenolysis via glucose-mediated inhibition of glycogen phosphorylase (3), with minimal net hepatic glycogen synthesis (1). The combination of hyperinsulinemia and hyperglycemia maximizes net hepatic glycogen synthesis (1). Other nutrients further optimize net hepatic glycogen synthesis, such as activation of glucokinase by catalytic quantities of fructose (4).Hepatic insulin action requires a coordinated relay of intracellular signals (Figure 1 and ref. 5). Insulin activates the insulin receptor tyrosine kinase (IRTK), with subsequent activation of kinases including 3-phosphoinositide-dependent kinase-1 (PDK1) and mTORC2 (6), which converge on Akt phosphorylation (6-8). The pattern of insulin delivery may also impact Akt phosphorylation, with pulsatile portal delivery (which better mimics physiology) leading to greater activation than continuous, fixed insulin delivery (9). Activation of Akt is the integral result of multiple inputs to regulate hepatic glucose and lipid metabolism. This model has been used to explain how insulin suppresses hepatic glucose production via (i) lowering expression of gluconeogenic enzymes via phosphorylation and nuclear exclusion of FOXO1 and (ii) inactivation of glycogen synthase kinase 3β (GSK3β), which permits the activation of glycogen synthase.Recent studies challenge the primacy of the Akt/GSK3β/ glycogen synthase branch in the regulation ...

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Section: Discussionmentioning

confidence: 88%

mentioning

confidence: 99%

The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux

Samuel¹,

Shulman²

2016

Journal of Clinical Investigation

967

819

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“…S3. The most active compound was the ethanolamine NSC13316 (37), which had an IC 50 of 2.7 μM in Rv3378c inhibition (Fig. S4).…”

Section: Resultsmentioning

confidence: 99%

“…We then tested NSC13316 (37) and these analogs (Fig. S5) for uncoupling activity in the EcIMV and MsIMV assays, finding that vacquinol (37) had an ∼12-13 μM IC 50 (Fig. S4).…”

Section: Resultsmentioning

confidence: 99%

“…Niclosamide (12) has been proposed as a lead for the treatment of type II diabetes (34), and it is also an inhibitor of breast cancer stem-like cells (35) and an inhibitor of Pseudomonas aeruginosa quorum sensing (36). There has also been very recent interest in the development of DNP analogs such as DNP methyl ether (37), for treating diabetes, and of controlledrelease DNP formulations (38) as mild hepatic mitochondrial uncouplers for treating hypertriglyceridemia, insulin resistance, hepatic steatosis, and diabetes. Niclosamide (12) and tizoxanide (14) are both FDA-approved, and closantel (15) is an anthelmintic uncoupler in veterinary use, and all could provide leads for new and improved inhibitors that target other pathogens.…”

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confidence: 99%

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Antiinfectives targeting enzymes and the proton motive force

Feng

Zhu

Schurig-Briccio

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

139

169

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There is a growing need for new antibiotics. Compounds that target the proton motive force (PMF), uncouplers, represent one possible class of compounds that might be developed because they are already used to treat parasitic infections, and there is interest in their use for the treatment of other diseases, such as diabetes. Here, we tested a series of compounds, most with known antiinfective activity, for uncoupler activity. Many cationic amphiphiles tested positive, and some targeted isoprenoid biosynthesis or affected lipid bilayer structure. As an example, we found that clomiphene, a recently discovered undecaprenyl diphosphate synthase inhibitor active against Staphylococcus aureus, is an uncoupler. Using in silico screening, we then found that the anti-glioblastoma multiforme drug lead vacquinol is an inhibitor of Mycobacterium tuberculosis tuberculosinyl adenosine synthase, as well as being an uncoupler. Because vacquinol is also an inhibitor of M. tuberculosis cell growth, we used similarity searches based on the vacquinol structure, finding analogs with potent (∼0.5-2 μg/mL) activity against M. tuberculosis and S. aureus. Our results give a logical explanation of the observation that most new tuberculosis drug leads discovered by phenotypic screens and genome sequencing are highly lipophilic (logP ∼5.7) bases with membrane targets because such species are expected to partition into hydrophobic membranes, inhibiting membrane proteins, in addition to collapsing the PMF. This multiple targeting is expected to be of importance in overcoming the development of drug resistance because targeting membrane physical properties is expected to be less susceptible to the development of resistance.T here is a need for new antibiotics, due to the increase in drug resistance (1, 2). For example, some studies report that by 2050, absent major improvements in drug discovery and use, more individuals will die from drug-resistant bacterial infections than from cancer, resulting in a cumulative effect on global gross domestic product of as much as 100 trillion dollars (3, 4). To discover new drugs, new targets, leads, concepts, and implementations are needed (5, 6).Currently, one major cause of death from bacterial infections is tuberculosis (TB) (7), where very highly drug-resistant strains have been found (8). Therapy is lengthy, even with drug-sensitive strains, and requires combination therapies with four drugs. Two recent TB drugs/drug leads (9-11) are TMC207 [bedaquiline (1); Sirturo] and SQ109 (2) (Fig. 1). Bedaquiline (1) targets the Mycobacterium tuberculosis ATP synthase (9) whereas SQ109 (2) has been proposed to target MmpL3 (mycobacterial membrane protein large 3), a trehalose monomycolate transporter essential for cell wall biosynthesis (12). SQ109 (2) is a lipophilic base containing an adamantyl "headgroup" connected via an ethylene diamine "linker" to a geranyl (C 10 ) "side chain," and in recent work (13), we synthesized a series of 11 analogs of SQ109 (2) finding that the ethanolamine (3) was more potent th...

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Structural investigations on the mitochondrial uncouplers niclosamide and FCCP

Ng,

Song,

Tan

et al. 2024

FEBS Open Bio

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There has been renewed interest in using mitochondrial uncoupler compounds such as niclosamide and carbonyl cyanide p‐(trifluoromethoxy)phenylhydrazone (FCCP) for the treatment of obesity, hepatosteatosis and diseases where oxidative stress plays a role. However, both FCCP and niclosamide have undesirable effects that are not due to mitochondrial uncoupling, such as inhibition of mitochondrial oxygen consumption by FCCP and induction of DNA damage by niclosamide. Through structure–activity analysis, we identified FCCP analogues that do not inhibit mitochondrial oxygen consumption but still provided good, although less potent, uncoupling activity. We also characterized the functional role of the niclosamide 4′‐nitro group, the phenolic hydroxy group and the anilide amino group in mediating uncoupling activity. Our structural investigations provide important information that will aid further drug development.

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Reversal of Hypertriglyceridemia, Fatty Liver Disease, and Insulin Resistance by a Liver-Targeted Mitochondrial Uncoupler

Cited by 194 publications

References 23 publications

The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux

The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux

Antiinfectives targeting enzymes and the proton motive force

Structural investigations on the mitochondrial uncouplers niclosamide and FCCP

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