Genetic Liver-Specific AMPK Activation Protects against Diet-Induced Obesity and NAFLD

Garcia, Daniel; Hellberg, Kristina; Chaix, Amandine; Wallace, Martina; Herzig, Sébastien; Badur, Mehmet G.; Lin, Terry; Shokhirev, Maxim N.; Pinto, Antônio Frederico Michel; Ross, Debbie S.; Saghatelian, Alan; Panda, Satchidananda; Dow, Lukas E.; Metallo, Christian M.; Shaw, Reuben J.

doi:10.1016/j.celrep.2018.12.036

Cited by 230 publications

(191 citation statements)

References 49 publications

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“…This may be one of the mechanisms by which hepatic deletion of ANGPTL4 improves metabolic function following HFD-induced obesity. This hypothesis is supported by the recent studies on the overexpression of AMPK in the mouse liver (46,47). Data from these studies indicate that activation of AMPK in the liver decreases lipid deposition not only in the liver, but also in the AT.…”

Section: Discussionmentioning

confidence: 55%

Liver-specific suppression of ANGPTL4 improves obesity-associated diabetes and mitigates atherosclerosis in mice

Singh

Chaube

Canfrán‐Duque

et al. 2020

Preprint

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Angiopoietin-like 4 (ANGPTL4) is a major regulator of lipoprotein lipase (LPL) activity, which is responsible for maintaining optimal levels of circulating triacylglycerol (TAG) for distribution to different tissues including the adipose tissues (ATs), heart, muscle and liver. Dysregulation of trafficking and portioning of fatty acids (FA) can promote ectopic lipid accumulation in metabolic tissues such as the liver, ultimately leading to systemic metabolic dysfunction. To investigate how ANGPTL4 regulates hepatic lipid and glucose metabolism, we generated liver-specific ANGPTL4 knockout mice (LKO). Using metabolic turnover studies, we demonstrate that hepatic ANGPTL4 deficiency facilitates catabolism of TAG-rich lipoprotein (TRL) remnants in the liver via increased hepatic lipase (HL) activity, which results in a significant reduction in circulating TAG and cholesterol levels. Deletion of hepatocyte ANGPTL4 protects against diet-induce obesity, glucose intolerance, liver steatosis, and atherogenesis. Mechanistically, we demonstrate that absence of ANGPTL4 in hepatocytes promotes FA uptake which results in increased FA oxidation, ROS production, and AMPK activation. Finally, we demonstrate the utility of a targeted pharmacologic therapy that specifically inhibits ANGPTL4 in the liver and protects against diet-induced obesity, dyslipidemia, glucose intolerance, and liver damage without causing any of the deleterious effects previously observed with neutralizing antibodies.

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Section: Discussionmentioning

confidence: 55%

Liver-specific suppression of ANGPTL4 improves obesity-associated diabetes and mitigates atherosclerosis in mice

Singh

Chaube

Canfrán‐Duque

et al. 2020

Preprint

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“…Genetic (10)(11)(12)(13) and pharmacological (7) activation of AMPK in liver improves hepatic steatosis. This led to the hypothesis that AMPK activation could be useful for the treatment of early stages of NAFLD.…”

Section: Discussionmentioning

confidence: 99%

“…(6,8) We confirmed these data and thereby validated our genetic models by the demonstration that the loss of AMPK in skeletal muscle, but not in liver, attenuated the beneficial effect of the compound on glucose tolerance. Genetic models have provided contradictory results concerning whether the stimulation of AMPK affects whole-body fat oxidation, (11)(12)(13) and pharmacological studies with selective activators have not yet been carried out. As shown here, AMPK activation by compound 1 lowered the RQ and stimulated fat oxidation in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…(6,8) Both the pharmacological and genetic activation of hepatic AMPK improve steatosis, suggesting that AMPK activation could also be a useful strategy for the treatment of early stages of NAFLD. (7,(10)(11)(12)(13) In the present study, we characterized a compound that activates AMPK in both liver and muscle. This compound improves both hepatic steatosis and fibrosis, and reduces the onset of HCC in a rodent model of NASH.…”

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confidence: 99%

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Activation of Adenosine Monophosphate—Activated Protein Kinase Reduces the Onset of Diet‐Induced Hepatocellular Carcinoma in Mice

et al. 2020

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The worldwide obesity and type 2 diabetes epidemics have led to an increase in nonalcoholic fatty liver disease (NAFLD). NAFLD covers a spectrum of hepatic pathologies ranging from simple steatosis to nonalcoholic steatohepatitis, characterized by fibrosis and hepatic inflammation. Nonalcoholic steatohepatitis predisposes to the onset of hepatocellular carcinoma (HCC). Here, we characterized the effect of a pharmacological activator of the intracellular energy sensor adenosine monophosphate-activated protein kinase (AMPK) on NAFLD progression in a mouse model. The compound stimulated fat oxidation by activating AMPK in both liver and skeletal muscle, as revealed by indirect calorimetry. This translated into an ameliorated hepatic steatosis and reduced fibrosis progression in mice fed a diet high in fat, cholesterol, and fructose for 20 weeks. Feeding mice this diet for 80 weeks caused the onset of HCC. The administration of the AMPK activator for 12 weeks significantly reduced tumor incidence and size. Conclusion: Pharmacological activation of AMPK reduces NAFLD progression to HCC in preclinical models. (Hepatology Communications 2020;4:1056-1072). N onalcoholic fatty liver disease (NAFLD) is a chronic liver disease with increasing incidence driven by the pandemic spread of obesity and type 2 diabetes. NAFLD starts as simple steatosis and can develop into nonalcoholic steatohepatitis (NASH) with its hallmarks of steatosis, inflammation, and liver injury. NASH predisposes to the onset of liver cirrhosis and hepatocellular carcinoma (HCC). (1,2) NAFLD is the fastest-growing cause of HCC. (1,2) The molecular pathogenesis of NAFLD is not completely understood but is most likely multifactorial. It is favored by genetics as well as features of the metabolic syndrome,

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“…Targeting hepatic AMPK with an AMPK-specific small-molecule activator reduces liver steatosis and improves glucose disposal in obese mice 26,27 . Recently, Garcia et al 28 showed that liver-specific AMPK activation in DIO mice protects against liver steatosis.…”

Section: Discussionmentioning

confidence: 99%

New Insight into the Mechanisms of Ectopic Fat Deposition Improvement after Bariatric Surgery

et al. 2019

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non-alcoholic fatty-liver disease (nAfLD) is frequent in obese patients and represents a major risk factor for the development of diabetes and its complications. Bariatric surgery reverses the hepatic features of nAfLD. However, its mechanism of action remains elusive. We performed a comprehensive analysis of the mechanism leading to the improvement of nAfLD and insulin resistance in both obese rodents and humans following sleeve-gastrectomy (SG). SG improved insulin sensitivity and reduced hepatic and monocyte fat accumulation. importantly, fat accumulation in monocytes was well comparable to that in hepatocytes, suggesting that Plin2 levels in monocytes might be a noninvasive marker for the diagnosis of nAfLD. Both in vitro and in vivo studies demonstrated an effective metabolic regeneration of liver function and insulin sensitivity. Specifically, SG improved NAFLD significantly by enhancing AMP-activated protein kinase (AMPK) phosphorylation and chaperonemediated autophagy (CMA) that translate into the removal of Plin2 coating lipid droplets. This led to an increase in lipolysis and specific amelioration of hepatic insulin resistance. Elucidating the mechanism of impaired liver metabolism in obese subjects will help to design new strategies for the prevention and treatment of nAfLD. Non-alcoholic fatty liver disease (NAFLD) affects about 25% of the general population with peaks of 32% in Middle East and 30% in South America 1. A recent study demonstrated a linear relationship between body mass index (BMI) and NAFLD diagnosis, which was about 5-to 9-fold higher in subjects with a BMI between 30 and 32.5 kg/m 2 increasing to ca. 10-to 14-fold at BMIs of 37.5-40 kg/m 2 as compared with normal weight subjects 2. The prevalence of NAFLD in type 2 diabetes (T2D) is estimated to be around 60% 3. Non-alcoholic steatohepatitis (NASH) is a more aggressive form of NAFLD characterized by the presence of inflammatory cell infiltration and hepatocyte ballooning, which may further progress to cirrhosis and/or to hepatocellular carcinoma 1. Currently, there are no drugs approved to specifically treat NAFLD or NASH and thus weight loss remains the only approach. Bariatric surgery (BS) promotes T2D remission both in the short and in the long term 4-10 , as well as remission of both NAFLD and NASH 11. The major effect of SG is to reduce energy intake. It is known that a reduced energy intake activates AMP-activated protein kinase (AMPK) in its phosphorylated form that tends to counterbalance a low energy status and restores energy balance through the inhibition of ATP consumption and simultaneous promotion of

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Genetic Liver-Specific AMPK Activation Protects against Diet-Induced Obesity and NAFLD

Cited by 230 publications

References 49 publications

Liver-specific suppression of ANGPTL4 improves obesity-associated diabetes and mitigates atherosclerosis in mice

Liver-specific suppression of ANGPTL4 improves obesity-associated diabetes and mitigates atherosclerosis in mice

Activation of Adenosine Monophosphate—Activated Protein Kinase Reduces the Onset of Diet‐Induced Hepatocellular Carcinoma in Mice

New Insight into the Mechanisms of Ectopic Fat Deposition Improvement after Bariatric Surgery

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