Adaptation of Hepatic Mitochondrial Function in Humans with Non-Alcoholic Fatty Liver Is Lost in Steatohepatitis

Published on May 5, 2015in Cell Metabolism21.567
· DOI :10.1016/J.CMET.2015.04.004
Chrysi Koliaki10
Estimated H-index: 10
(HHU: University of Düsseldorf),
Julia Szendroedi32
Estimated H-index: 32
(HHU: University of Düsseldorf)
+ 9 AuthorsMichael Roden99
Estimated H-index: 99
(HHU: University of Düsseldorf)
Summary The association of hepatic mitochondrial function with insulin resistance and non-alcoholic fatty liver (NAFL) or steatohepatitis (NASH) remains unclear. This study applied high-resolution respirometry to directly quantify mitochondrial respiration in liver biopsies of obese insulin-resistant humans without (n = 18) or with (n = 16) histologically proven NAFL or with NASH (n = 7) compared to lean individuals (n = 12). Despite similar mitochondrial content, obese humans with or without NAFL had 4.3- to 5.0-fold higher maximal respiration rates in isolated mitochondria than lean persons. NASH patients featured higher mitochondrial mass, but 31%–40% lower maximal respiration, which associated with greater hepatic insulin resistance, mitochondrial uncoupling, and leaking activity. In NASH, augmented hepatic oxidative stress (H 2 O 2 , lipid peroxides) and oxidative DNA damage (8-OH-deoxyguanosine) was paralleled by reduced anti-oxidant defense capacity and increased inflammatory response. These data suggest adaptation of the liver ("hepatic mitochondrial flexibility") at early stages of obesity-related insulin resistance, which is subsequently lost in NASH.
Figures & Tables
📖 Papers frequently viewed together
387 Citations
2,218 Citations
13 Authors (David E. Kleiner, ..., Arun J. Sanyal)
6,417 Citations
#1Li Wang (Fourth Military Medical University)H-Index: 2
#2Xiaolei Liu (PSU: Pennsylvania State University)H-Index: 12
Last. Yuguang ShiH-Index: 42
view all 11 authors...
Oxidative stress causes mitochondrial dysfunction, which is implicated in the etiology of NAFLD and its progression to nonalcoholic steatohepatitis (NASH). Although the precise molecular mechanisms remain elusive, defective autophagy contributes to the pathogenesis of NAFLD, which is supported by the phenotypes of mouse models of impaired autophagy (1). Autophagy is required for the mitochondrial quality control process by engaging in a crosstalk with reactive oxygen species (ROS) to eliminate d...
58 CitationsSource
#1Tomas JelenikH-Index: 20
#2Gilles SéquarisH-Index: 2
Last. Michael RodenH-Index: 99
view all 16 authors...
Although insulin resistance is known to underlie type 2 diabetes, its role in the development of type 1 diabetes has been gaining increasing interest. In a model of type 1 diabetes, the nonobese diabetic (NOD) mouse, we found that insulin resistance driven by lipid- and glucose-independent mechanisms is already present in the liver of prediabetic mice. Hepatic insulin resistance is associated with a transient rise in mitochondrial respiration followed by increased production of lipid peroxides a...
40 CitationsSource
#1Chrysi Koliaki (HHU: University of Düsseldorf)H-Index: 10
#2Michael Roden (HHU: University of Düsseldorf)H-Index: 99
Alterations of hepatic mitochondrial function have been observed in states of insulin resistance and non-alcoholic fatty liver disease (NAFLD). Patients with overt type 2 diabetes mellitus (T2DM) can exhibit reduction in hepatic adenosine triphosphate (ATP) synthesis and impaired repletion of their hepatic ATP stores upon ATP depletion by fructose. Obesity and NAFLD may also associate with impaired ATP recovery after ATP-depleting challenges and augmented oxidative stress in the liver. On the ot...
77 CitationsSource
#1Stefan Freigang (EPFL: École Polytechnique Fédérale de Lausanne)H-Index: 24
#2Franziska Ampenberger (EPFL: École Polytechnique Fédérale de Lausanne)H-Index: 8
Last. Manfred Kopf (EPFL: École Polytechnique Fédérale de Lausanne)H-Index: 103
view all 7 authors...
Chronic inflammation is a fundamental aspect of metabolic disorders such as obesity, diabetes and cardiovascular disease. Cholesterol crystals are metabolic signals that trigger sterile inflammation in atherosclerosis, presumably by activating inflammasomes for IL-1β production. We found here that atherogenesis was mediated by IL-1α and we identified fatty acids as potent inducers of IL-1α-driven vascular inflammation. Fatty acids selectively stimulated the release of IL-1α but not of IL-1β by u...
222 CitationsSource
#1Santhosh Satapati (UTSW: University of Texas Southwestern Medical Center)H-Index: 19
#2Nishanth E. Sunny (UTSW: University of Texas Southwestern Medical Center)H-Index: 20
Last. Shawn C. BurgessH-Index: 53
view all 10 authors...
The manner in which insulin resistance impinges on hepatic mitochondrial function is complex. Although liver insulin resistance is associated with respiratory dysfunction, the effect on fat oxidation remains controversial, and biosynthetic pathways that traverse mitochondria are actually increased. The tricarboxylic acid (TCA) cycle is the site of terminal fat oxidation, chief source of electrons for respiration, and a metabolic progenitor of gluconeogenesis. Therefore, we tested whether insulin...
241 CitationsSource
#1Jakob D. Wikstrom (BU: Boston University)H-Index: 22
#2Samuel B. Sereda (BU: Boston University)H-Index: 5
Last. Orian S. Shirihai (BU: Boston University)H-Index: 66
view all 9 authors...
Background The pancreatic beta cell is unique in its response to nutrient by increased fuel oxidation. Recent studies have demonstrated that oxygen consumption rate (OCR) may be a valuable predictor of islet quality and long term nutrient responsiveness. To date, high-throughput and user-friendly assays for islet respiration are lacking. The aim of this study was to develop such an assay and to examine bioenergetic efficiency of rodent and human islets.
91 CitationsSource
#1Kenneth Cusi (UF: University of Florida)H-Index: 71
As obesity reaches epidemic proportions, nonalcoholic fatty liver disease (NAFLD) is becoming a frequent cause of patient referral to gastroenterologists. There is a close link between dysfunctional adipose tissue in NAFLD and common conditions such as metabolic syndrome, type 2 diabetes mellitus, and cardiovascular disease. This review focuses on the pathophysiology of interactions between adipose tissue and target organs in obesity and the resulting clinical implications for the management of ...
564 CitationsSource
#1Nishanth E. Sunny (UTSW: University of Texas Southwestern Medical Center)H-Index: 20
#2Elizabeth J. Parks (UTSW: University of Texas Southwestern Medical Center)H-Index: 39
Last. Shawn C. Burgess (UTSW: University of Texas Southwestern Medical Center)H-Index: 53
view all 4 authors...
Summary Approximately one-third of the U.S. population has nonalcoholic fatty liver disease (NAFLD), a condition closely associated with insulin resistance and increased risk of liver injury. Dysregulated mitochondrial metabolism is central in these disorders, but the manner and degree of dysregulation are disputed. This study tested whether humans with NAFLD have abnormal in vivo hepatic mitochondrial metabolism. Subjects with low (3.0%) and high (17%) intrahepatic triglyceride (IHTG) were stud...
387 CitationsSource
#1Anu Suomalainen (UH: University of Helsinki)H-Index: 72
#2Jenni M. Elo (UH: University of Helsinki)H-Index: 3
Last. Henna Tyynismaa (UH: University of Helsinki)H-Index: 31
view all 25 authors...
Summary Background Muscle biopsy is the gold standard for diagnosis of mitochondrial disorders because of the lack of sensitive biomarkers in serum. Fibroblast growth factor 21 (FGF-21) is a growth factor with regulatory roles in lipid metabolism and the starvation response, and concentrations are raised in skeletal muscle and serum in mice with mitochondrial respiratory chain deficiencies. We investigated in a retrospective diagnostic study whether FGF-21 could be a biomarker for human mitochon...
270 CitationsSource
#1Agnieszka Gornicka (Case Western Reserve University)H-Index: 6
#2Gareth Morris-StiffH-Index: 37
Last. Ariel E. FeldsteinH-Index: 76
view all 6 authors...
Abstract Oxidative stress is a core abnormality responsible for disease progression in nonalcoholic steatohepatitis (NASH). However, the relevant pathways that contribute to oxidative damage in vivo remain poorly understood. Here we explore the gene-expression patterns related to oxidative stress, antioxidant defense, and reactive oxygen metabolism in an established dietary murine model of NASH. C57BL/6 mice were placed on either a methionine- and choline-deficient (MCD) or a control (CTL) diet ...
41 CitationsSource
Cited By412
#1Hee Jeong Chun (SNU: Seoul National University)
#2Yeon Joo Shim (SNU: Seoul National University)
Last. Young Hye Kwon (SNU: Seoul National University)H-Index: 9
view all 3 authors...
Nonalcoholic fatty liver disease (NAFLD) is one of the major causes of hepatocellular carcinoma (HCC). Although the intracellular cholesterol accumulation has been demonstrated to regulate the gene expression responsible for steatohepatitis, the role played by cholesterol in the development of NAFLD-associated HCC has not been fully elucidated. In this study, using microarray analysis, we investigated the molecular mechanisms governing cholesterol-mediated progression of NAFLD. To ensure hepatic...
#1Lucia Mastrototaro (HHU: University of Düsseldorf)H-Index: 12
#2Michael Roden (HHU: University of Düsseldorf)H-Index: 99
Abstract null null Insulin resistance is a common feature of obesity and type 2 diabetes, but novel approaches of diabetes subtyping (clustering) revealed variable degrees of insulin resistance in people with diabetes. Specifically, the severe insulin resistant diabetes (SIRD) subtype not only exhibits metabolic abnormalities, but also bears a higher risk for cardiovascular, renal and hepatic comorbidities. In humans, insulin resistance comprises dysfunctional adipose tissue, lipotoxic insulin s...
#1Yuan Gao (Capital Medical University)H-Index: 3
#2Wei Shi (Chinese PLA General Hospital)H-Index: 27
Last. Jun Zhao
view all 12 authors...
#1Justyna KubackaH-Index: 1
#2Paulina CembrowskaH-Index: 2
Last. Anna StefańskaH-Index: 10
view all 4 authors...
We examined the glycemic status-stratified relationships between total serum branched-chain amino acid (BCAA) concentrations and cardiometabolic risk factors in middle-aged Caucasian women. The study included 349 women divided into 2 subgroups: a normoglycemic group (NG, n = 184) and a dysglycemic group (DG, n = 165). Blood samples, anthropometric parameters, and blood pressure were measured. HOMA-IR, albumin-corrected calcium (CCa), and fatty liver index (FLI) were calculated. BCAA concentratio...
#2Antonella OrlandoH-Index: 19
Last. Vito PesceH-Index: 25
view all 8 authors...
Nonalcoholic fatty liver disease (NAFLD) is the leading liver chronic disease featuring hepatic steatosis. Mitochondrial β-oxidation participates in the derangement of lipid metabolism at the basis of NAFLD, and mitochondrial oxidative stress contributes to the onset of the disease. We evaluated the presence and effects of mitochondrial oxidative stress in the liver from rats fed a high-fat plus fructose (HF-F) diet inducing NAFLD. Supplementation with dehydroepiandrosterone (DHEA), a multitarge...
#2Yi Long Huang (NCTU: National Chiao Tung University)
Last. Ting-Fen Tsai (NHRI: National Health Research Institutes)H-Index: 35
view all 5 authors...
Cisd2 (CDGSH iron sulfur domain 2) is a pro-longevity gene that extends the lifespan and health span of mice, ameliorates age-associated structural damage and limits functional decline in multiple tissues. Non-alcoholic fatty liver disease (NAFLD), which plays an important role in age-related liver disorders, is the most common liver disease worldwide. However, no medicines that can be used to specifically and effectively treat NAFLD are currently approved for this disease. Our aim was to provid...
#1D. Scheiber (HHU: University of Düsseldorf)H-Index: 3
#2Elric Zweck (HHU: University of Düsseldorf)H-Index: 6
Last. Felicitas EscherH-Index: 30
view all 16 authors...
AIMS Acute cellular rejection (ACR) following heart transplantation (HTX) is associated with long-term graft loss and increased mortality. Disturbed mitochondrial bioenergetics have been identified as pathophysiological drivers in heart failure, but their role in ACR remains unclear. We aimed to prove functional disturbances of myocardial bioenergetics in human heart transplant recipients with mild ACR by assessing myocardial mitochondrial respiration using high-resolution respirometry, digital ...
#1Qianrang Lu (ZJU: Zhejiang University)
#2Xinyao Tian (ZJU: Zhejiang University)H-Index: 2
Last. Shusen Zheng (ZJU: Zhejiang University)H-Index: 64
view all 9 authors...
Nonalcoholic fatty liver disease (NAFLD) is often accompanied by systemic metabolic disorders such as hyperglycemia, insulin resistance, and obesity. The relationship between NAFLD and systemic metabolic disorders has been well reviewed before, however the metabolic changes that occur in hepatocyte itself have not been discussed. In NAFLD, many metabolic pathways have undergone significant changes in hepatocyte, such as enhanced glycolysis, gluconeogenesis, lactate production, tricarboxylic acid...
#2Mi Yeon Lee (SKKU: Sungkyunkwan University)H-Index: 8
Last. Won Young Lee (SKKU: Sungkyunkwan University)H-Index: 61
view all 0 authors...
BACKGROUND AND AIMS Fibrosis progression is the most important prognostic factor, and insulin resistance is one of the main mechanisms associated with fibrosis progression in patients with nonalcoholic fatty liver disease (NAFLD). We evaluate the association between baseline insulin resistance and future fibrosis progression in patients with NAFLD without diabetes. APPROACH AND RESULTS This retrospective longitudinal study with 8-year follow-up period included 32,606 (men, 83%) participants aged...
#1Mohammad Irshad Reza (Central Drug Research Institute)H-Index: 3
#2Anees A. Syed (AcSIR: Academy of Scientific and Innovative Research)H-Index: 8
Last. Jiaur R. Gayen (Central Drug Research Institute)H-Index: 26
view all 5 authors...
Abstract null null Aims null Mitochondrial dysfunction is among the key factors for the advancement of hepatic steatosis to NAFLD and NASH. Pancreastatin (PST: human ChgA250-301) is a dysglycemic hormone, previously reported to promote steatosis and inflammation in various animal models of metabolic disorders. Recently, we observed PST deregulates energy expenditure and mitochondrial functioning in perimenopausal rats. In the current study, we aimed to decipher the role of PST instigated altered...