Mitochondrial Adaptation in Nonalcoholic Fatty Liver Disease: Novel Mechanisms and Treatment Strategies

Sunny, Nishanth E.; Bril, Fernando; Cusi, Kenneth

doi:10.1016/j.tem.2016.11.006

Cited by 254 publications

(246 citation statements)

References 84 publications

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“…Individuals with type 2 diabetes have a higher risk of developing NASH, and the disease has a more severe prognosis [1, 2]. The mechanisms responsible for progression from NAFL to NASH may involve lipotoxicity, oxidative stress, endoplasmic reticulum stress and mitochondrial dysfunction [3, 4]. Moreover, there are common genetic variants predisposing to both NAFL and NASH, including the well-documented I148M variant of the patatin-like phospholipase domain-containing protein 3 ( PNPLA3 ) gene [5].…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, there are common genetic variants predisposing to both NAFL and NASH, including the well-documented I148M variant of the patatin-like phospholipase domain-containing protein 3 ( PNPLA3 ) gene [5]. Currently, there are no approved drugs for treatment of NASH, and the recommended treatment consists of weight loss and exercise [2, 3]. …”

Section: Introductionmentioning

confidence: 99%

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Effects of dapagliflozin and n-3 carboxylic acids on non-alcoholic fatty liver disease in people with type 2 diabetes: a double-blind randomised placebo-controlled study

et al. 2018

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Aims/hypothesisThe EFFECT-II study aimed to investigate the effects of dapagliflozin and omega-3 (n-3) carboxylic acids (OM-3CA), individually or combined, on liver fat content in individuals with type 2 diabetes and non-alcoholic fatty liver disease (NAFLD).MethodsThis randomised placebo-controlled double-blind parallel-group study was performed at five clinical research centres at university hospitals in Sweden. 84 participants with type 2 diabetes and NAFLD were randomly assigned 1:1:1:1 to four treatments by a centralised randomisation system, and all participants as well as investigators and staff involved in the study conduct and analyses were blinded to treatments. Each group received oral doses of one of the following: 10 mg dapagliflozin (n = 21), 4 g OM-3CA (n = 20), a combination of both (n = 22) or placebo (n = 21). The primary endpoint was liver fat content assessed by MRI (proton density fat fraction [PDFF]) and, in addition, total liver volume and markers of glucose and lipid metabolism as well as of hepatocyte injury and oxidative stress were assessed at baseline and after 12 weeks of treatment (completion of the trial).ResultsParticipants had a mean age of 65.5 years (SD 5.9), BMI 31.2 kg/m2 (3.5) and liver PDFF 18% (9.3). All active treatments significantly reduced liver PDFF from baseline, relative changes: OM-3CA, −15%; dapagliflozin, −13%; OM-3CA + dapagliflozin, −21%. Only the combination treatment reduced liver PDFF (p = 0.046) and total liver fat volume (relative change, −24%, p = 0.037) in comparison with placebo. There was an interaction between the PNPLA3 I148M polymorphism and change in liver PDFF in the active treatment groups (p = 0.03). Dapagliflozin monotherapy, but not the combination with OM-3CA, reduced the levels of hepatocyte injury biomarkers, including alanine aminotransferase, aspartate aminotransferase, γ-glutamyl transferase (γ-GT), cytokeratin (CK) 18-M30 and CK 18-M65 and plasma fibroblast growth factor 21 (FGF21). Changes in γ-GT correlated with changes in liver PDFF (ρ = 0.53, p = 0.02). Dapagliflozin alone and in combination with OM-3CA improved glucose control and reduced body weight and abdominal fat volumes. Fatty acid oxidative stress biomarkers were not affected by treatments. There were no new or unexpected adverse events compared with previous studies with these treatments.Conclusions/interpretationCombined treatment with dapagliflozin and OM-3CA significantly reduced liver fat content. Dapagliflozin monotherapy reduced all measured hepatocyte injury biomarkers and FGF21, suggesting a disease-modifying effect in NAFLD.Trial registration:ClinicalTrials.gov NCT02279407Funding:The study was funded by AstraZeneca.Electronic supplementary materialThe online version of this article (10.1007/s00125-018-4675-2) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effects of dapagliflozin and n-3 carboxylic acids on non-alcoholic fatty liver disease in people with type 2 diabetes: a double-blind randomised placebo-controlled study

et al. 2018

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“…The transition from relatively benign hepatic steatosis to NASH marks a critical step in NAFLD progression that has important clinical implications, particularly the risk for end-stage liver disease, such as cirrhosis and hepatocellular carcinoma (5,6). Multiple pathogenic drivers have been implicated in NASH initiation and progression, including oxidative stress, mitochondrial dysfunction, lipotoxicity, and immune cell activation (7)(8)(9)(10). Despite this, the physiological mechanisms that defend against NASH progression remain poorly defined.…”

Section: Introductionmentioning

confidence: 99%

Hepatic neuregulin 4 signaling defines an endocrine checkpoint for steatosis-to-NASH progression

Guo

Zhang

Chen

et al. 2017

Journal of Clinical Investigation

144

133

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“…, hypoxia and immunologic stimuli) [48,49,50] and the loss of antioxidant defense system that includes enzymes (e.g., SOD, CAT and GSH-Px) and small molecular antioxidant scavengers (e.g., vitamin E, N -acetylcysteine and α-lipoic acid) [51,52]. The oxidative stress or ROS causes cellular damage by reacting with and/or denaturing cellular macromolecules including lipid, protein and nucleic acids, and/or even mediating or activating intracellular death signaling pathways [53], which plays an important role in the pathogenesis and progression of diabetes, fatty liver disease and their associated CKD including DN [52,54,55,56]. Grape products are rich in antioxidant chemicals, such as phenolic, flavonoid, and anthocyanidin [57,58,59], and exhibit anti-oxidative activities in both humans and animals [37,60,61].…”

Section: Discussionmentioning

confidence: 99%

Daily Intake of Grape Powder Prevents the Progression of Kidney Disease in Obese Type 2 Diabetic ZSF1 Rats

et al. 2017

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Individuals living with metabolic syndrome (MetS) such as diabetes and obesity are at high risk for developing chronic kidney disease (CKD). This study investigated the beneficial effect of whole grape powder (WGP) diet on MetS-associated CKD. Obese diabetic ZSF1 rats, a kidney disease model with MetS, were fed WGP (5%, w/w) diet for six months. Kidney disease was determined using blood and urine chemical analyses, and histology. When compared to Vehicle controls, WGP intake did not change the rat bodyweight, but lowered their kidney, liver and spleen weight, which were in parallel with the lower serum glucose and the higher albumin or albumin/globin ratio. More importantly, WGP intake improved the renal function as urination and proteinuria decreased, or it prevented kidney tissue damage in these diabetic rats. The renal protection of WGP diet was associated with up-regulation of antioxidants (Dhcr24, Gstk1, Prdx2, Sod2, Gpx1 and Gpx4) and downregulation of Txnip (for ROS production) in the kidneys. Furthermore, addition of grape extract reduced H2O2-induced cell death of cultured podocytes. In conclusion, daily intake of WGP reduces the progression of kidney disease in obese diabetic rats, suggesting a protective function of antioxidant-rich grape diet against CKD in the setting of MetS.

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Mitochondrial Adaptation in Nonalcoholic Fatty Liver Disease: Novel Mechanisms and Treatment Strategies

Cited by 254 publications

References 84 publications

Effects of dapagliflozin and n-3 carboxylic acids on non-alcoholic fatty liver disease in people with type 2 diabetes: a double-blind randomised placebo-controlled study

Effects of dapagliflozin and n-3 carboxylic acids on non-alcoholic fatty liver disease in people with type 2 diabetes: a double-blind randomised placebo-controlled study

Hepatic neuregulin 4 signaling defines an endocrine checkpoint for steatosis-to-NASH progression

Daily Intake of Grape Powder Prevents the Progression of Kidney Disease in Obese Type 2 Diabetic ZSF1 Rats

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