From NAFLD to NASH to cirrhosis—new insights into disease mechanisms
01 Nov 2013-Nature Reviews Gastroenterology & Hepatology (Nature Publishing Group)-Vol. 10, Iss: 11, pp 627-636
TL;DR: This Review focuses on recently uncovered aspects of the genetic, biochemical, immunological and molecular events that are responsible for the development and progression of this highly prevalent and potentially serious disease.
Abstract: NAFLD has evolved as a serious public health problem in the USA and around the world. In fact, NASH-the most serious form of NAFLD-is predicted to become the leading cause of liver transplantation in the USA by the year 2020. The pathogenesis of NAFLD and NASH, in particular the mechanisms responsible for liver injury and fibrosis, is the result of a complex interplay between host and environmental factors, and is at the centre of intense investigation. In this Review, we focus on recently uncovered aspects of the genetic, biochemical, immunological and molecular events that are responsible for the development and progression of this highly prevalent and potentially serious disease. These studies bring new insight into this complex disorder and have led to the development of novel therapeutic and diagnostic strategies that might enable a personalized approach in the management of this disease.
Citations
More filters
TL;DR: Based on a meta-analysis of studies of paired liver biopsy studies, liver fibrosis progresses in patients with NAFL and NASH.
1,165 citations
TL;DR: The past three decades of steady progress in understanding liver fibrosis have contributed to an emerging translational success story, with realistic hopes for antifibrotic therapies to treat patients with chronic liver disease in the near future.
Abstract: Reversibility of hepatic fibrosis and cirrhosis following antiviral therapy for hepatitis B or C has advanced the prospect of developing antifibrotic therapies for patients with chronic liver diseases, especially non-alcoholic steatohepatitis. Mechanisms of fibrosis have focused on hepatic stellate cells, which become fibrogenic myofibroblasts during injury through ‘activation’, and are at the nexus of efforts to define novel drug targets. Recent studies have clarified pathways of stellate cell gene regulation and epigenetics, emerging pathways of fibrosis regression through the recruitment and amplification of fibrolytic macrophages, nuanced responses of discrete inflammatory cell subsets and the identification of the ‘ductular reaction’ as a marker of severe injury and repair. Based on our expanded knowledge of fibrosis pathogenesis, attention is now directed towards strategies for antifibrotic therapies and regulatory challenges for conducting clinical trials with these agents. New therapies are attempting to: 1) Control or cure the primary disease or reduce tissue injury; 2) Target receptor-ligand interactions and intracellular signaling; 3) Inhibit fibrogenesis; and 4) Promote resolution of fibrosis. Progress is urgently needed in validating non-invasive markers of fibrosis progression and regression that can supplant biopsy and shorten the duration of clinical trials. Both scientific and clinical challenges remain, however the past three decades of steady progress in understanding liver fibrosis have contributed to an emerging translational success story, with realistic hopes for antifibrotic therapies to treat patients with chronic liver disease in the near future.
705 citations
TL;DR: The multifaceted and complex interactions between the liver and T2DM are described, which show some efficacy in the treatment of NASH.
Abstract: The association between NAFLD and diabetes mellitus has garnered increasing attention in the past few years. In this Review, Tilg and colleagues explore in detail the molecular mechanisms linking NAFLD and diabetes mellitus, and discuss clinical aspects arising from the interaction of both diseases. The liver constitutes a key organ in systemic metabolism, contributing substantially to the development of insulin resistance and type 2 diabetes mellitus (T2DM). The mechanisms underlying these processes are not entirely understood, but involve hepatic fat accumulation, alterations of energy metabolism and inflammatory signals derived from various cell types including immune cells. Lipotoxins, mitochondrial function, cytokines and adipocytokines have been proposed to play a major part in both NAFLD and T2DM. Patients with NAFLD are commonly insulin resistant. On the other hand, a large number of patients with T2DM develop NAFLD with its inflammatory complication, NASH. The high incidence of NASH in patients with T2DM leads to further complications, such as liver cirrhosis and hepatocellular carcinoma, which are increasingly recognized. Therapeutic concepts such as thiazolidinediones (glitazones) for treating T2DM also show some efficacy in the treatment of NASH. This Review will describe the multifaceted and complex interactions between the liver and T2DM.
629 citations
Cites background from "From NAFLD to NASH to cirrhosis—new..."
...SOCS1 and SOCS3 impair insulin signalling through ubiquitin-dependent degradation of IRS (3). c-Jun N-terminal kinase (JNK, also known as mitogen activated protein kinase) represents another important inhibitory kinase of IRS that is activated in response to a variety of extracellular stimuli and cellular stressors such as oxidative and endoplasmic reticulum (ER) stress (4)....
[...]
...A shortterm highfat diet induced selective hepatic steatosis, along with impaired tyrosine phosphorylation of insulin receptor substrate (IRS)2 and increased activ ity of protein kinase C (PKC)ε and cJun Nterminal kinase 1 (JNK1; also known as mitogenactivated pro tein kinase 8) 40....
[...]
...1 3 4 5 6 2 Mitochondrion MEKs TRAF6TRAF2 JAK3 TAK1 and TAB2 PI3KPDK AdipoR cAMP ERK1 ERK2 RAS AMPK Insulin receptor STAT3 STAT3 SOCS1 SOCS3 JNKROS ER stress IKKβ Figure 2 | Inflammatory pathways affecting hepatic insulin resistance....
[...]
...Pro-inflammatory stimuli are counteracted by adipose-tissue-derived adiponectin via adiponectin receptor (AdipoR)1 and AdipoR2 (5), and by the anti-inflammatory IL-1 family member IL-37 (6) through so far unknown mechanisms....
[...]
...These studies identified subcutaneous adipose tissue as a major source of proinflammatory cytokines, in the face of similar expression in the sub cutaneous and visceral adipose tissue; therefore, high concentrations of proinflammatory signals from adi pose tissue might under certain circumstances induce hepatic insulin resistance via systemic inflammatory Nucleus Nature Reviews | Gastroenterology & Hepatology AKT PPARNF-κB AP-1 IRS1 IRS2 IL-6Rα IL-6Rβ TNFα RANKL Insulin Adiponectin IL-6 TNFR1 RANK IL-37 ?...
[...]
TL;DR: The metabolic benefits of Parabacteroides distasonis (PD) on decreasing weight gain, hyperglycemia, and hepatic steatosis in ob/ob and high-fat diet (HFD)-fed mice is demonstrated and succinate and secondary bile acids produced by P. distasonis played key roles in the modulation of host metabolism.
529 citations
TL;DR: It is shown that dysregulation of lipid metabolism in NAFLD causes a selective loss of intrahepatic CD4+ but not CD8+ T lymphocytes, leading to accelerated hepatocarcinogenesis, providing an unexpected link between lipid dysregulation and impaired anti-tumour surveillance.
Abstract: Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death. Non-alcoholic fatty liver disease (NAFLD) affects a large proportion of the US population and is considered to be a metabolic predisposition to liver cancer. However, the role of adaptive immune responses in NAFLD-promoted HCC is largely unknown. Here we show, in mouse models and human samples, that dysregulation of lipid metabolism in NAFLD causes a selective loss of intrahepatic CD4(+) but not CD8(+) T lymphocytes, leading to accelerated hepatocarcinogenesis. We also demonstrate that CD4(+) T lymphocytes have greater mitochondrial mass than CD8(+) T lymphocytes and generate higher levels of mitochondrially derived reactive oxygen species (ROS). Disruption of mitochondrial function by linoleic acid, a fatty acid accumulated in NAFLD, causes more oxidative damage than other free fatty acids such as palmitic acid, and mediates selective loss of intrahepatic CD4(+) T lymphocytes. In vivo blockade of ROS reversed NAFLD-induced hepatic CD4(+) T lymphocyte decrease and delayed NAFLD-promoted HCC. Our results provide an unexpected link between lipid dysregulation and impaired anti-tumour surveillance.
501 citations
References
More filters
TL;DR: The role of PRRs, their signaling pathways, and how they control inflammatory responses are discussed.
6,987 citations
TL;DR: It is concluded that the LPS/CD14 system sets the tone of insulin sensitivity and the onset of diabetes and obesity and lowering plasma LPS concentration could be a potent strategy for the control of metabolic diseases.
Abstract: Diabetes and obesity are two metabolic diseases characterized by insulin resistance and a low-grade inflammation. Seeking an inflammatory factor causative of the onset of insulin resistance, obesity, and diabetes, we have identified bacterial lipopolysaccharide (LPS) as a triggering factor. We found that normal endotoxemia increased or decreased during the fed or fasted state, respectively, on a nutritional basis and that a 4-week high-fat diet chronically increased plasma LPS concentration two to three times, a threshold that we have defined as metabolic endotoxemia. Importantly, a high-fat diet increased the proportion of an LPS-containing microbiota in the gut. When metabolic endotoxemia was induced for 4 weeks in mice through continuous subcutaneous infusion of LPS, fasted glycemia and insulinemia and whole-body, liver, and adipose tissue weight gain were increased to a similar extent as in high-fat-fed mice. In addition, adipose tissue F4/80-positive cells and markers of inflammation, and liver triglyceride content, were increased. Furthermore, liver, but not whole-body, insulin resistance was detected in LPS-infused mice. CD14 mutant mice resisted most of the LPS and high-fat diet-induced features of metabolic diseases. This new finding demonstrates that metabolic endotoxemia dysregulates the inflammatory tone and triggers body weight gain and diabetes. We conclude that the LPS/CD14 system sets the tone of insulin sensitivity and the onset of diabetes and obesity. Lowering plasma LPS concentration could be a potent strategy for the control of metabolic diseases.
5,032 citations
TL;DR: The outcome of cirrhosis and liver-related death is not uniform across the spectrum of nonalcoholic fatty liver, and poor outcomes are more frequent in patients in whom biopsies show ballooning degeneration and Mallory hyaline or fibrosis.
3,167 citations
TL;DR: A previously unknown function for autophagy in regulating intracellular lipid stores (macrolipophagy) is identified that could have important implications for human diseases with lipid over-accumulation such as those that comprise the metabolic syndrome.
Abstract: The intracellular storage and utilization of lipids are critical to maintain cellular energy homeostasis. During nutrient deprivation, cellular lipids stored as triglycerides in lipid droplets are hydrolysed into fatty acids for energy. A second cellular response to starvation is the induction of autophagy, which delivers intracellular proteins and organelles sequestered in double-membrane vesicles (autophagosomes) to lysosomes for degradation and use as an energy source. Lipolysis and autophagy share similarities in regulation and function but are not known to be interrelated. Here we show a previously unknown function for autophagy in regulating intracellular lipid stores (macrolipophagy). Lipid droplets and autophagic components associated during nutrient deprivation, and inhibition of autophagy in cultured hepatocytes and mouse liver increased triglyceride storage in lipid droplets. This study identifies a critical function for autophagy in lipid metabolism that could have important implications for human diseases with lipid over-accumulation such as those that comprise the metabolic syndrome.
3,091 citations
TL;DR: Mortality among community-diagnosed NAFLD patients is higher than the general population and is associated with older age, impaired fasting glucose, and cirrhosis, although the absolute risk is low.
2,681 citations