Nonalcoholic fatty liver disease: A main driver of insulin resistance or a dangerous liaison?

Gruben, Nanda; Shiri-Sverdlov, Ronit; Koonen, Debby P. Y.; Hofker, Marten H.

doi:10.1016/j.bbadis.2014.08.004

Cited by 116 publications

(97 citation statements)

References 112 publications

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“…Low grade inflammation is also a characteristic of advanced hepatic steatosis or nonalcoholic steatohepatitis (NASH) (Sabio et al 2008, Yang et al 2009, Gruben et al 2014. Fatty liver in HL K/K mice was accompanied by augmented hepatic inflammation (macrophage content and Mcp1 mRNA levels) and by increased systemic inflammation including higher circulating MCP1 levels, monocytosis and higher percentage of T-cells.…”

Section: Discussionmentioning

confidence: 99%

“…NAFLD is frequently associated with hepatic IR and MetS (Sabio et al 2008, Yang et al 2009, Gruben et al 2014. Thus, while IR development increases triglyceride accumulation in the liver (Samuel et al 2010, Samuel & Shulman 2012, fatty liver produces an excess of glucose and triglycerides, which are key components in IR and MetS (Anstee et al 2013, Yki-Jarvinen 2014.…”

Section: Discussionmentioning

confidence: 99%

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Hepatic lipase deficiency produces glucose intolerance, inflammation and hepatic steatosis

Andrés‐Blasco¹,

Herrero-Cervera²,

Vinué³

et al. 2015

Journal of Endocrinology

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Metabolic syndrome and type 2 diabetes mellitus constitute a major problem to global health, and their incidence is increasing at an alarming rate. Non-alcoholic fatty liver disease, which affects up to 90% of obese people and nearly 70% of the overweight, is commonly associated with MetS characteristics such as obesity, insulin resistance, hypertension and dyslipidemia. In the present study, we demonstrate that hepatic lipase (HL)-inactivation in mice fed with a high-fat, high-cholesterol diet produced dyslipidemia including hypercholesterolemia, hypertriglyceridemia and increased non-esterified fatty acid levels. These changes were accompanied by glucose intolerance, pancreatic and hepatic inflammation and steatosis. In addition, compared with WT mice, HL K/K mice exhibited enhanced circulating MCP1 levels, monocytosis and higher percentage of CD4CTh17C cells. Consistent with increased inflammation, livers from HL K/K mice had augmented activation of the stress SAPK/JNK-and p38-pathways compared with the activation levels of the kinases in livers from WT mice. Analysis of HL K/K and WT mice fed regular chow diet showed dyslipidemia and glucose intolerance in HL K/K mice without any other changes in inflammation or hepatic steatosis. Altogether, these results indicate that dyslipidemia induced by HL-deficiency in combination with a high-fat, high-cholesterol diet promotes hepatic steatosis and inflammation in mice which are, at least in part, mediated by the activation of the stress SAPK/JNK-and p38-pathways. Future studies are warranted to asses the viability of therapeutic strategies based on the modulation of these kinases to reduce hepatic steatosis associated to lipase dysfunction.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Hepatic lipase deficiency produces glucose intolerance, inflammation and hepatic steatosis

Andrés‐Blasco¹,

Herrero-Cervera²,

Vinué³

et al. 2015

Journal of Endocrinology

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“…Current treatment options are weight loss, resistance training and high dose vitamin E therapy [16,30]. NAFLD is closely associated with metabolic syndrome, which includes central obesity, hypertension, elevated blood glucose and dyslipidemia [16,31,32].…”

Section: Non-alcoholic Fatty Liver Disease (Nafld)mentioning

confidence: 99%

Chemerin in Liver Diseases

2014

Endocrinol Metab Synd

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Chemerin is a chemoattractant protein and moreover has a role in adipogenesis, angiogenesis and glucose homeostasis. Chemerin is primarily synthesized and secreted by adipocytes and hepatocytes. Chemerin receptors chemokine-like receptor 1 (CMKLR1), G-protein coupled receptor 1 (GPR1) and CC-motif chemokine receptorlike 2 (CCRL2) are all expressed in the liver suggesting that chemerin may be relevant in liver physiology and pathophysiology. Non-alcoholic fatty liver disease (NAFLD) is associated with obesity and is the most common cause of chronic liver injury. NAFLD and chronic hepatitis C virus infection are risk factors for hepatocellular carcinoma. Hepatic and serum chemerin have been analyzed in human and rodent NAFLD, in patients with chronic hepatitis C and patients with hepatocellular carcinoma. Chemerin, GPR1 and CMKLR1 deficient mice have been used to elucidate the role of these proteins in body weight gain and glucose homeostasis. The regulation of chemerin and CMKLR1 by adipokines, hormones and cytokines relevant in liver diseases has been studied in hepatocytes. The data published so far are briefly summarized herein. Current experimental findings do not provide evidence for a crucial role of chemerin in chronic liver diseases and further research is needed to evaluate a possible protective function of this protein in hepatocellular carcinoma.

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“…Clearly, insulin resistance in general can cause hepatic steatosis, whereas hepatic steatosis may promote insulin resistance under select circumstances [11]; alternatively, both steatosis and insulin resistance just reflect the presence of obesity [12], a fact that could be of critical importance when designing targeted therapy for NASH.…”

Section: A Treatments Directed At Mechanisms Of Hepatocellular Lipidmentioning

confidence: 99%

New Medical Treatment Strategies for Nonalcoholic Steatohepatitis

Fuchs

2015

Curr Treat Options Gastro

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Nonalcoholic steatohepatitis (NASH) is a severe form of fatty liver disease unrelated to chronic alcohol consumption. As nonalcoholic fatty liver disease (NAFLD) has reached epidemic proportions and is becoming the most common cause for chronic liver disease, NASH likely will replace chronic hepatitis C as leading indication for liver cirrhosis and liver transplantation in this decade. Despite this alarming trend, effective treatment is lacking and continues to rely on dietary interventions and physical exercise, known to be of limited effect. Hence, there is an urgent need for safe pharmacologic therapy that successfully reverses or prevents progression of liver injury and fibrosis in patients with NASH. Employing emerging concepts of disease development and progression that involve in parallel ongoing events originating from the liver, adipose tissue, and intestine will ultimately promote the development of effective agents for targeted therapies for NASH. Novel agents must be safe, optimally dosed, and finally pass clinical trials providing proof of concept and efficacy. In the case of NASH, trial design is not necessarily straightforward as surrogate end points to predict clinical benefits are not yet established. The level of unmet needs for NASH goes however even beyond therapeutic agents and also includes patient and physician awareness. This article focuses on identifying potential pathophysiology-guided targets for medical therapy of NASH.

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Nonalcoholic fatty liver disease: A main driver of insulin resistance or a dangerous liaison?

Cited by 116 publications

References 112 publications

Hepatic lipase deficiency produces glucose intolerance, inflammation and hepatic steatosis

Hepatic lipase deficiency produces glucose intolerance, inflammation and hepatic steatosis

Chemerin in Liver Diseases

New Medical Treatment Strategies for Nonalcoholic Steatohepatitis

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