Mechanisms of NAFLD development and therapeutic strategies

Nature Medicine, Journal Year: 2018, Volume and Issue: 24(7), P. 908 - 922

Published: June 29, 2018

Language: Английский

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NAFLD: A multisystem disease

Journal of Hepatology, Journal Year: 2015, Volume and Issue: 62(1), P. S47 - S64

Published: April 1, 2015

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic in Western countries that predicted to become also frequent indication for transplantation by 2030. Over last decade, it has been shown clinical burden NAFLD not only confined liver-related morbidity and mortality, but there now growing evidence a multisystem disease, affecting extra-hepatic organs regulatory pathways. For example, increases risk type 2 diabetes mellitus (T2DM), cardiovascular (CVD) cardiac diseases, kidney (CKD). Although primary pathology affects hepatic structure function mortality from cirrhosis, failure hepatocellular carcinoma, majority deaths among patients are attributable CVD. This narrative review focuses on rapidly expanding body supports concept as disease. The discusses factors involved progression linking with other such T2DM, CVD, diseases CKD. will discuss treatments these discussed elsewhere this issue Journal. review, PubMed was searched articles using keywords "non-alcoholic disease" or "fatty liver" combined "diabetes", "cardiovascular (or cardiac) disease", mortality" "chronic between 1990 2014. Articles published languages than English were excluded.

Language: Английский

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Mechanisms of Insulin Action and Insulin Resistance

Physiological Reviews, Journal Year: 2018, Volume and Issue: 98(4), P. 2133 - 2223

Published: Aug. 1, 2018

The 1921 discovery of insulin was a Big Bang from which vast and expanding universe research into action resistance has issued. In the intervening century, some discoveries have matured, coalescing solid fertile ground for clinical application; others remain incompletely investigated scientifically controversial. Here, we attempt to synthesize this work guide further mechanistic investigation inform development novel therapies type 2 diabetes (T2D). rational such necessitates detailed knowledge one key pathophysiological processes involved in T2D: resistance. Understanding resistance, turn, requires normal action. review, both physiology pathophysiology are described, focusing on three target tissues: skeletal muscle, liver, white adipose tissue. We aim develop an integrated physiological perspective, placing intricate signaling effectors that carry out cell-autonomous response context tissue-specific functions generate coordinated organismal response. First, section II, effects direct, tissue reviewed, beginning at receptor working downstream. Section III considers critical underappreciated role crosstalk whole body action, especially essential interaction between lipolysis hepatic gluconeogenesis. is then described IV. Special attention given pathways become resistant setting chronic overnutrition, alternative explanation phenomenon ‟selective resistanceˮ presented. Sections V, VI, VII critically examine evidence against several putative mediators V reviews linking bioactive lipids diacylglycerol, ceramide, acylcarnitine resistance; VI impact nutrient stresses endoplasmic reticulum mitochondria discusses non-cell autonomous factors proposed induce including inflammatory mediators, branched-chain amino acids, adipokines, hepatokines. Finally, VIII, propose model links these final common metabolite-driven gluconeogenesis ectopic lipid accumulation.

Language: Английский

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Type 2 diabetes mellitus

Nature Reviews Disease Primers, Journal Year: 2015, Volume and Issue: 1(1)

Published: July 22, 2015

Language: Английский

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Impact of the gut microbiota on inflammation, obesity, and metabolic disease

Genome Medicine, Journal Year: 2016, Volume and Issue: 8(1)

Published: April 20, 2016

The human gut harbors more than 100 trillion microbial cells, which have an essential role in metabolic regulation via their symbiotic interactions with the host. Altered ecosystems been associated increased and immune disorders animals humans. Molecular linking microbiota host energy metabolism, lipid accumulation, immunity also identified. However, exact mechanisms that link specific variations composition of development obesity diseases humans remain obscure owing to complex etiology these pathologies. In this review, we discuss current knowledge about mechanistic between microbiota, system context disease, a focus on importance axis links microbes inflammation. Finally, therapeutic approaches aimed at reshaping ecosystem regulate related pathologies, as well challenges area.

Language: Английский

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Adipose Tissue Dysfunction as Determinant of Obesity-Associated Metabolic Complications

International Journal of Molecular Sciences, Journal Year: 2019, Volume and Issue: 20(9), P. 2358 - 2358

Published: May 13, 2019

Obesity is a critical risk factor for the development of type 2 diabetes (T2D), and its prevalence rising worldwide. White adipose tissue (WAT) has crucial role in regulating systemic energy homeostasis. Adipose expands by combination an increase adipocyte size (hypertrophy) number (hyperplasia). The recruitment differentiation precursor cells subcutaneous (SAT), rather than merely inflating cells, would be protective from obesity-associated metabolic complications. In metabolically unhealthy obesity, storage capacity SAT, largest WAT depot, limited, further caloric overload leads to fat accumulation ectopic tissues (e.g., liver, skeletal muscle, heart) visceral depots, event commonly defined as "lipotoxicity." Excessive lipid local inflammation insulin resistance (IR). Indeed, overnutrition triggers uncontrolled inflammatory responses WAT, leading chronic low-grade inflammation, therefore fostering progression IR. This review summarizes current knowledge on dysfunction obesity associated abnormalities, such A better understanding mechanisms expansion required future therapeutic approaches

Language: Английский

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Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease

Cellular and Molecular Life Sciences, Journal Year: 2018, Volume and Issue: 75(18), P. 3313 - 3327

Published: June 23, 2018

Non-alcoholic fatty liver disease (NAFLD) is currently the world's most common disease, estimated to affect up one-fourth of population. Hallmarked by hepatic steatosis, NAFLD associated with a multitude detrimental effects and increased mortality. This narrative review investigates molecular mechanisms steatosis in NAFLD, focusing on four major pathways contributing lipid homeostasis liver. Hepatic consequence acquisition exceeding disposal, i.e., uptake acids de novo lipogenesis surpassing acid oxidation export. In are increased, while compensatory enhancement insufficient normalizing levels may even promote cellular damage progression inducing oxidative stress, especially compromised mitochondrial function peroxisomes cytochromes. While export initially increases, it plateaus decrease progression, sustaining accumulation lipids. Fueled lipo-apoptosis, leads systemic metabolic disarray that adversely affects multiple organs, placing abnormal metabolism close relation many current life-style-related diseases.

Language: Английский

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Adipose Tissue Distribution, Inflammation and Its Metabolic Consequences, Including Diabetes and Cardiovascular Disease

Frontiers in Cardiovascular Medicine, Journal Year: 2020, Volume and Issue: 7

Published: Feb. 25, 2020

Adipose tissue plays essential roles in maintaining lipid and glucose homeostasis. To date several types of adipose have been identified, namely white, brown, beige, that reside various specific anatomical locations throughout the body. The cellular composition, secretome, location these depots define their function health metabolic disease. In obesity, becomes dysfunctional, promoting a pro-inflammatory, hyperlipidemic insulin resistant environment contributes to type 2 diabetes mellitus (T2DM). Concurrently, similar features result from dysfunction also promote cardiovascular disease (CVD) by mechanisms can be augmented T2DM. which dysfunctional simultaneously T2DM CVD, focusing on depot-specific adipokines, inflammatory profiles, metabolism, will focus this review. impact CVD treatment strategies body weight discussed.

Language: Английский

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Regulation of hepatic glucose metabolism in health and disease

Nature Reviews Endocrinology, Journal Year: 2017, Volume and Issue: 13(10), P. 572 - 587

Published: July 21, 2017

Language: Английский

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Insulin resistance: Review of the underlying molecular mechanisms

Journal of Cellular Physiology, Journal Year: 2018, Volume and Issue: 234(6), P. 8152 - 8161

Published: Oct. 14, 2018

Abstract Most human cells utilize glucose as the primary substrate, cellular uptake requiring insulin. Insulin signaling is therefore critical for these tissues. However, decrease in insulin sensitivity due to disruption of various molecular pathways causes resistance (IR). IR underpins many metabolic disorders such type 2 diabetes and syndrome, impairments disrupting entry into adipocytes, skeletal muscle cells. Although exact underlying cause has not been fully elucidated, a number major mechanisms, including oxidative stress, inflammation, receptor mutations, endoplasmic reticulum mitochondrial dysfunction have suggested. In this review, we consider role mechanisms play development IR.

Language: Английский

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