Hepatic ceramides dissociate steatosis and insulin resistance in patients with non-alcoholic fatty liver disease

Luukkonen, Panu K.; Zhou, You; Sädevirta, Sanja; Leivonen, Marja; Arola, Johanna; Orešič, Matej; Hyötyläinen, Tuulia; Yki‐Järvinen, Hannele

doi:10.1016/j.jhep.2016.01.002

Cited by 367 publications

(385 citation statements)

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“…1. Modified with permission from [7] contrast to 'obese/metabolic NAFLD', where saturated and monounsaturated triacylglycerols and NEFA predominate [47]. Insulin resistance inducing ceramides synthesised by the de novo ceramide synthetic pathway are increased in 'obese/metabolic NAFLD' but not in NAFLD associated with the I148M variant ('PNPLA3 NAFLD').…”

Section: Heterogeneity Of Nafld: Nafld But No Metabolic Syndromementioning

confidence: 99%

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Diagnosis of non-alcoholic fatty liver disease (NAFLD)

Yki‐Järvinen

2016

Diabetologia

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Section: Heterogeneity Of Nafld: Nafld But No Metabolic Syndromementioning

confidence: 99%

“…Such selected patients might include those who have NAFLD but do not have dyslipidaemia or insulin resistance. Given that both the gene variants and obesity/metabolic syndrome are common, many patients of course have 'double trouble' [47].…”

Section: Heterogeneity Of Nafld: Nafld But No Metabolic Syndromementioning

confidence: 99%

Diagnosis of non-alcoholic fatty liver disease (NAFLD)

Yki‐Järvinen

2016

Diabetologia

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“…Although IHTGs are commonly associated with IR, triglycerides (TGs) themselves are inert and do not confer IR (7). We have previously shown in humans that IR cosegregates with hepatic ceramides, independent of IHTGs and obesity (7).…”

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confidence: 99%

Saturated Fat Is More Metabolically Harmful for the Human Liver Than Unsaturated Fat or Simple Sugars

et al. 2018

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OBJECTIVE Nonalcoholic fatty liver disease (i.e., increased intrahepatic triglyceride [IHTG] content), predisposes to type 2 diabetes and cardiovascular disease. Adipose tissue lipolysis and hepatic de novo lipogenesis (DNL) are the main pathways contributing to IHTG. We hypothesized that dietary macronutrient composition influences the pathways, mediators, and magnitude of weight gain-induced changes in IHTG. RESEARCH DESIGN AND METHODS We overfed 38 overweight subjects (age 48 ± 2 years, BMI 31 ± 1 kg/m2, liver fat 4.7 ± 0.9%) 1,000 extra kcal/day of saturated (SAT) or unsaturated (UNSAT) fat or simple sugars (CARB) for 3 weeks. We measured IHTG (1H-MRS), pathways contributing to IHTG (lipolysis ([2H5]glycerol) and DNL (2H2O) basally and during euglycemic hyperinsulinemia), insulin resistance, endotoxemia, plasma ceramides, and adipose tissue gene expression at 0 and 3 weeks. RESULTS Overfeeding SAT increased IHTG more (+55%) than UNSAT (+15%, P < 0.05). CARB increased IHTG (+33%) by stimulating DNL (+98%). SAT significantly increased while UNSAT decreased lipolysis. SAT induced insulin resistance and endotoxemia and significantly increased multiple plasma ceramides. The diets had distinct effects on adipose tissue gene expression. CONCLUSIONS Macronutrient composition of excess energy influences pathways of IHTG: CARB increases DNL, while SAT increases and UNSAT decreases lipolysis. SAT induced the greatest increase in IHTG, insulin resistance, and harmful ceramides. Decreased intakes of SAT could be beneficial in reducing IHTG and the associated risk of diabetes.

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“…In such study, the liver lipidome was analysed from tissue obtained from liver biopsies in 125 subjects who were divided into similarly sized groups based on median HOMA-IR ('high vs. low HOMA-IR', n=62 and n=63) or PNPLA3 genotype (PNPLA3 148MM/MI, n=61 vs. PNPLA3 148II, n=64). The results of this study showed that for the 'high HOMA-IR' vs. 'low HOMA-IR' group comparison, in the more insulin resistant group (the high HOMA-IR group) the liver was markedly enriched with saturated and monounsaturated triacylglycerols and free fatty acids, dihydroceramides (markers of de novo ceramide synthesis) and ceramides [49]. Clearly, the results of this study suggest that further work is needed to better understand hepatic processing and re-modelling of liver lipids such as ceramides, and how ceramides cause hepatic insulin resistance in people with genotypes such as PNPLA3 148MM that is known to influence liver disease in NAFLD.…”

Section: Hepatic Lipid Accumulation Insulin Resistance Insulin Cleamentioning

confidence: 79%

“…Although in the past, it was thought that ceramide was simply a structural molecule, there is some evidence that increases in membrane ceramide may cause insulin resistance [48], potentially providing a mechanism to link hepatic lipid metabolism and hepatic inflammation. Recently, it has been suggested that differences in ceramide metabolism may also explain why NAFLD with insulin resistance is associated with features of the metabolic syndrome; whereas the patatin-like phospholipase domain-containing protein 3 (PNPLA3 148MM) genotype associated with NAFLD, is not associated with metabolic syndrome (and thereby with no increased risk of type 2 diabetes) [49]. In such study, the liver lipidome was analysed from tissue obtained from liver biopsies in 125 subjects who were divided into similarly sized groups based on median HOMA-IR ('high vs. low HOMA-IR', n=62 and n=63) or PNPLA3 genotype (PNPLA3 148MM/MI, n=61 vs. PNPLA3 148II, n=64).…”

Section: Hepatic Lipid Accumulation Insulin Resistance Insulin Cleamentioning

confidence: 99%

Risk of type 2 diabetes in patients with non-alcoholic fatty liver disease: Causal association or epiphenomenon?

Targher

Marchesini

Byrne

2016

Diabetes & Metabolism

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Nonalcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver diseases worldwide, causing considerable liverrelated mortality and morbidity. Over the last 10 years, it has also become increasingly evident that NAFLD is a multisystem disease, affecting many extra-hepatic organ systems and interacting with the regulation of multiple metabolic pathways. NAFLD is potentially involved in the aetiology and pathogenesis of type 2 diabetes via its direct contribution to hepatic/peripheral insulin resistance and the systemic release of multiple hepatokines that may adversely affect glucose metabolism and insulin action and secretion. In this updated review, we discuss the rapidly expanding body of clinical and epidemiological evidence that supports a strong link between NAFLD and the risk of developing type 2 diabetes. We also briefly examine the conventional and the more innovative pharmacological approaches for the treatment of NAFLD that may influence the risk of developing type 2 diabetes. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 2 AbstractNonalcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver diseases worldwide, causing considerable liver-related mortality and morbidity. Over the last 10 years, it has also become increasingly evident that NAFLD is a multisystem disease, affecting many extra-hepatic organ systems and interacting with the regulation of multiple metabolic pathways. NAFLD is potentially involved in the aetiology and pathogenesis of type 2 diabetes via its direct contribution to hepatic/peripheral insulin resistance and the systemic release of multiple hepatokines that may adversely affect glucose metabolism and insulin action and secretion. In this updated review, we discuss the rapidly expanding body of clinical and epidemiological evidence that supports a strong link between NAFLD and the risk of developing type 2 diabetes. We also briefly examine the conventional and the more innovative pharmacological approaches for the treatment of NAFLD that may influence the risk of developing type 2 diabetes.

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Hepatic ceramides dissociate steatosis and insulin resistance in patients with non-alcoholic fatty liver disease

Cited by 367 publications

References 47 publications

Diagnosis of non-alcoholic fatty liver disease (NAFLD)

Diagnosis of non-alcoholic fatty liver disease (NAFLD)

Saturated Fat Is More Metabolically Harmful for the Human Liver Than Unsaturated Fat or Simple Sugars

Risk of type 2 diabetes in patients with non-alcoholic fatty liver disease: Causal association or epiphenomenon?

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