The Role of Nuclear Receptors in the Pathophysiology, Natural Course, and Drug Treatment of NAFLD in Humans

Ballestri, Stefano; Nascimbeni, Fabio; Romagnoli, Dante; Baldelli, Enrica; Lonardo, Amedeo

doi:10.1007/s12325-016-0306-9

Cited by 77 publications

(48 citation statements)

References 256 publications

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“…The peroxisome proliferator-activated receptors- (PPAR-) alpha and delta are transcription factors finely regulating energetic fluxes and metabolic pathways [38]. PPAR- α is highly expressed in liver and regulates the rates of fatty acid catabolism and lipogenesis in response to nutritional demands.…”

Section: Discussionmentioning

confidence: 99%

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A Combination of Leucine, Metformin, and Sildenafil Treats Nonalcoholic Fatty Liver Disease and Steatohepatitis in Mice

Bruckbauer¹,

Banerjee²,

et al. 2016

International Journal of Hepatology

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Sirt1, AMPK, and eNOS modulate hepatic energy metabolism and inflammation and are key players in the development of NASH. L-leucine, an allosteric Sirt1 activator, synergizes with low doses of metformin or sildenafil on the AMPK-eNOS-Sirt1 pathway to reverse mild NAFLD in preclinical mouse models. Here we tested a possible multicomponent synergy to yield greater therapeutic efficacy in NAFLD/NASH. Liver cells and macrophages or an atherogenic diet induced NASH mouse model was treated with two-way and three-way combinations. The three-way combination Sild-Met-Leu increased hepatic fatty acid oxidation and reduced lipogenic gene expression and inflammatory marker in vitro. In mice, Sild-Met-Leu reduced the diet induced increases of ALT, TGFβ, PAI-1, IL1β, and TNFα, hepatic collagen expression, and nearly completely reversed hepatocyte ballooning and triglyceride accumulation, while all two-way combinations had only modest effects. Therefore, these data provide preclinical evidence for therapeutic efficacy of Sild-Met-Leu in the treatment of NAFLD and NASH.

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Section: Discussionmentioning

confidence: 99%

“…PPAR- δ is constitutively expressed and regulates β -oxidation in muscle. In the liver, it controls hepatic glucose and lipoprotein metabolism and exerts anti-inflammatory effects [38, 43]. Beneficial effects of PPAR- δ agonists on improvement of hepatic steatosis and inflammation have been reported in mouse models of NASH [44].…”

Section: Discussionmentioning

confidence: 99%

A Combination of Leucine, Metformin, and Sildenafil Treats Nonalcoholic Fatty Liver Disease and Steatohepatitis in Mice

Bruckbauer¹,

Banerjee²,

et al. 2016

International Journal of Hepatology

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“…However, recent studies have demonstrated that simple steatosis can progress to NASH and that both conditions progress to advanced fibrosis, though this occurs at a much slower pace for simple steatosis than for NASH[16,25-27]. The severity of hepatic fibrosis, rather than NASH, largely dictates the prognosis of liver-related outcomes in NAFLD[21,28,29]. …”

Section: Nafldmentioning

confidence: 99%

Fatty liver is associated with an increased risk of diabetes and cardiovascular disease - Evidence from three different disease models: NAFLD, HCV and HIV

Lonardo¹,

Ballestri²,

Guaraldi³

et al. 2016

WJG

Self Cite

101

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Fatty liver, which frequently coexists with necro-inflammatory and fibrotic changes, may occur in the setting of nonalcoholic fatty liver disease (NAFLD) and chronic infections due to either hepatitis C virus (HCV) or human immunodeficiency virus (HIV). These three pathologic conditions are associated with an increased prevalence and incidence of cardiovascular disease (CVD) and type 2 diabetes (T2D). In this multidisciplinary clinical review, we aim to discuss the ever-expanding wealth of clinical and epidemiological evidence supporting a key role of fatty liver in the development of T2D and CVD in patients with NAFLD and in those with HCV or HIV infections. For each of these three common diseases, the epidemiological features, pathophysiologic mechanisms and clinical implications of the presence of fatty liver in predicting the risk of incident T2D and CVD are examined in depth. Collectively, the data discussed in this updated review, which follows an innovative comparative approach, further reinforce the conclusion that the presence of fatty/inflamed/fibrotic liver might be a shared important determinant for the development of T2D and CVD in patients with NAFLD, HCV or HIV. This review may also open new avenues in the clinical and research arenas and paves the way for the planning of future, well-designed prospective and intervention studies.

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“…Risk factors of NAFLD and NASH include type 2 DM, central obesity, hypertension, dyslipidaemia, lack of sleep and physical inactivity . More recently, it has been proposed that dysregulation of nuclear receptors such as peroxisome proliferator‐activated receptors, liver X receptors and farnesoid X receptors, which are transcriptional factors that regulate several metabolic pathways, plays a significant role in the development and progression of NAFLD …”

Section: Introductionmentioning

confidence: 99%

Hyperuricaemia and risk of nonalcoholic fatty liver disease: A meta‐analysis

Wijarnpreecha

Panjawatanan

Lekuthai

et al. 2016

Liver International

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The Role of Nuclear Receptors in the Pathophysiology, Natural Course, and Drug Treatment of NAFLD in Humans

Abstract: ABSTRACT

Cited by 77 publications

References 256 publications

A Combination of Leucine, Metformin, and Sildenafil Treats Nonalcoholic Fatty Liver Disease and Steatohepatitis in Mice

A Combination of Leucine, Metformin, and Sildenafil Treats Nonalcoholic Fatty Liver Disease and Steatohepatitis in Mice

Fatty liver is associated with an increased risk of diabetes and cardiovascular disease - Evidence from three different disease models: NAFLD, HCV and HIV

Hyperuricaemia and risk of nonalcoholic fatty liver disease: A meta‐analysis

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