Adiponectin knockout mice on high fat diet develop fibrosing steatohepatitis

Asano, Takeharu; Watanabe, Kiyotaka; Kubota, Naoto; Gunji, Toshiaki; Omata, Masao; Kadowaki, Takashi; Ohnishi, S. Tsuyoshi

doi:10.1111/j.1440-1746.2009.06039.x

Cited by 91 publications

(68 citation statements)

References 49 publications

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“…Adiponectin deficient mice are more susceptible to high fat diet mediated hepatic triglyceride storage, hepatic insulin resistance and inflammation (Asano et al, 2009;Yano et al, 2008), and further studies using CMKLR1 deficient mice are needed to define the role of this receptor in NAFLD. Adiponectin effects are transduced by two receptors, AdipoR1 and AdipoR2, which are both expressed in hepatocytes Yamauchi et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Adiponectin upregulates hepatocyte CMKLR1 which is reduced in human fatty liver

Wanninger¹,

Walter²,

Bauer³

et al. 2012

Z Gastroenterol

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Chemokine-like receptor 1 (CMKLR1) ligands chemerin and resolvin E1 are suggested to have a role in non-alcoholic fatty liver disease (NAFLD). Here, expression of CMKLR1 in liver cells and NAFLD was studied. CMKLR1 was detected in primary human hepatocytes (PHH), Kupffer cells, bile-duct cells and hepatic stellate cells. In human and rodent fatty liver and in fibrotic liver of mice fed a methionine-choline deficient diet CMKLR1 was reduced. Hepatocytes are the major cells in the liver and effects of adipokines, cytokines and lipids on CMKLR1 in PHH were analyzed. Increased cellular triglyceride or cholesterol content, lipopolysaccharide, IL-6, TNF and leptin did not influence CMKLR1 levels in PHH whereas profibrotic TGFβ tended to reduce CMKLR1. Adiponectin strongly upregulated CMKLR1 mRNA and protein in PHH and hepatic CMKLR1 when injected into wild type mice. Further, CMKLR1 was suppressed in the liver of adiponectin deficient mice. These data indicate that low CMKLR1 in NAFLD may partly result from reduced adiponectin activity.

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Section: Discussionmentioning

confidence: 99%

Adiponectin upregulates hepatocyte CMKLR1 which is reduced in human fatty liver

Wanninger¹,

Walter²,

Bauer³

et al. 2012

Z Gastroenterol

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“…Literature data indicate that adiponectin has predominantly hepato-protective and anti-fibrogenic effects in conditions of CLD [61], as shown in particular in the experimental model of fibrosis induced by chronic administration of CCl 4 [62]. Adiponectin has likely a protective role also in the context of NAFLD/NASH as shown by experiments in which pericellular fibrosis was found to be more severe in adiponectin-deficient mice (i.v., vs wild type mice) fed a high-fat diet [63]. Moreover, adiponectin has been reported to delay the progression of experimental NASH towards cirrhosis and hepatocellular carcinoma [64].…”

Section: Adipokinesmentioning

confidence: 99%

Cellular and molecular mechanisms in liver fibrogenesis

Novo

Cannito

Paternostro

et al. 2014

Archives of Biochemistry and Biophysics

178

194

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“…Increases in leptin and resistin are associated with insulin resistance, while adiponectin is associated with increased insulin sensitivity. Mice lacking adiponectin are prone to hepatic steatosis and hepatic insulin resistance (91,92). While overexpression of adiponectin in ob/ob mice leads to increased adiposity, the improvement in adipose function lowered adipose inflammation, circulating lipids, and hepatic DAG content and improved hepatic insulin action (93).…”

Section: Adipose Insulin Resistancementioning

confidence: 99%

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

Samuel¹,

Shulman²

2016

Journal of Clinical Investigation

1,018

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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Adiponectin knockout mice on high fat diet develop fibrosing steatohepatitis

Abstract: Adiponectin may play a protective role in the progression of NASH in the early stages by suppressing tumor necrosis factor-alpha expression and liver fibrosis.

Cited by 91 publications

References 49 publications

Adiponectin upregulates hepatocyte CMKLR1 which is reduced in human fatty liver

Adiponectin upregulates hepatocyte CMKLR1 which is reduced in human fatty liver

Cellular and molecular mechanisms in liver fibrogenesis

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

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