Alterations in Liver ATP Homeostasis in Human Nonalcoholic Steatohepatitis

Cortez‐Pinto, Helena; Chatham, John C.; Chacko, V. P.; Arnold, Cheryl; Rashid, Asif; Diehl, Anna Mae

doi:10.1001/jama.282.17.1659

Cited by 451 publications

(312 citation statements)

References 25 publications

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“…Here, we have drastically reduced the number of metabolites that were necessary to diagnose NASH from a metabolomic profile of roughly 540 lipids and amino acids19 to a panel of 28 TGs. TGs were chosen because NAFLD is characterized by an abnormal regulation of liver TG homeostasis42, 43 and the observation that changes in the molecular species of liver TGs are mirrored in serum 44…”

Section: Discussionmentioning

confidence: 99%

Metabolomic‐based noninvasive serum test to diagnose nonalcoholic steatohepatitis: Results from discovery and validation cohorts

Mayo

Crespo

Martínez‐Arranz

et al. 2018

Hepatology Communications

139

114

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Nonalcoholic fatty liver disease (NAFLD) is the most common type of chronic liver disease worldwide and includes a broad spectrum of histologic phenotypes, ranging from simple hepatic steatosis or nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH). While liver biopsy is the reference gold standard for NAFLD diagnosis and staging, it has limitations due to its sampling variability, invasive nature, and high cost. Thus, there is a need for noninvasive biomarkers that are robust, reliable, and cost effective. In this study, we measured 540 lipids and amino acids in serum samples from biopsy‐proven subjects with normal liver (NL), NAFL, and NASH. Using logistic regression analysis, we identified two panels of triglycerides that could first discriminate between NAFLD and NL and second between NASH and NAFL. These noninvasive tests were compared to blinded histology as a reference standard. We performed these tests in an original cohort of 467 patients with NAFLD (90 NL, 246 NAFL, and 131 NASH) that was subsequently validated in a separate cohort of 192 patients (7 NL, 109 NAFL, 76 NASH). The diagnostic performances of the validated tests showed an area under the receiver operating characteristic curve, sensitivity, and specificity of 0.88 ± 0.05, 0.94, and 0.57, respectively, for the discrimination between NAFLD and NL and 0.79 ± 0.04, 0.70, and 0.81, respectively, for the discrimination between NASH and NAFL. When the analysis was performed excluding patients with glucose levels >136 mg/dL, the area under the receiver operating characteristic curve for the discrimination between NASH and NAFL increased to 0.81 ± 0.04 with sensitivity and specificity of 0.73 and 0.80, respectively. Conclusion: The assessed noninvasive lipidomic serum tests distinguish between NAFLD and NL and between NASH and NAFL with high accuracy. (Hepatology Communications 2018;2:807‐820)

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Section: Discussionmentioning

confidence: 99%

Metabolomic‐based noninvasive serum test to diagnose nonalcoholic steatohepatitis: Results from discovery and validation cohorts

Mayo

Crespo

Martínez‐Arranz

et al. 2018

Hepatology Communications

139

114

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“…The time course of ATP resynthesis upon fructose infusion has been used as a more direct marker of hepatic mitochondrial function but apparently becomes less efficient with increasing BMI. 31 Previous liver 31 P MRS studies were limited by the inability to estimate absolute concentrations, making it necessary to express the intensities of phosphorus signals as ratios to that of another metabolite and/or to the assumed concentration of a metabolite. Consequently, qualitative MRS would fail to detect these alterations in the presences of parallel increases or decreases of metabolites as shown in alcoholic liver disease.…”

Section: Discussionmentioning

confidence: 99%

“…Volunteers were scanned in the prone position with the 10-cm-diameter linearly polarized surface coil positioned under the lateral aspect of the liver in a 3-T whole-body scanner (Medspec S30/80; Bruker Biospin, Ettlingen, Germany). The 31 P three-dimensional kspace-weighted MRS imaging (MRSI) localization technique (13 ϫ 13 ϫ 13 matrix; field of view: 20 cm ϫ 20 cm ϫ 20 cm; repetition time: 1 second) with adiabatic excitation pulse was used to acquire 31 P spectra (Fig. 1).…”

Section: Methodsmentioning

confidence: 99%

Abnormal Hepatic Energy Homeostasis in Type 2 Diabetes†

et al. 2009

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Increased hepatocellular lipids relate to insulin resistance and are typical for individuals with type 2 diabetes mellitus (T2DM). Steatosis and T2DM have been further associated with impaired muscular adenosine triphosphate (ATP) turnover indicating reduced mitochondrial fitness. Thus, we tested the hypothesis that hepatic energy metabolism could be impaired even in metabolically well-controlled T2DM. We measured hepatic lipid volume fraction (HLVF) and absolute concentrations of ␥ATP, inorganic phosphate (Pi), phosphomonoesters and phosphodiesters using noninvasive 1 H/ 31 P magnetic resonance spectroscopy in individuals with T2DM (58 ؎ 6 years, 27 ؎ 3 kg/m 2 ), and age-matched and body mass index-matched (mCON; 61 ؎ 4 years, 26 ؎ 4 kg/m 2 ) and young lean humans (yCON; 25 ؎ 3 years, 22 ؎ 2 kg/m 2 , P < 0.005, P < 0.05 versus T2DM and mCON). Insulin-mediated whole-body glucose disposal (M) and endogenous glucose production (iEGP) were assessed during euglycemic-hyperinsulinemic clamps. Individuals with T2DM had 26% and 23% lower ␥ATP (1.68 ؎ 0.11; 2.26 ؎ 0.20; 2.20 ؎ 0.09 mmol/L; P < 0.05) than mCON and yCON individuals, respectively. Further, they had 28% and 31% lower Pi than did individuals from the mCON and yCON groups (0.96 ؎ 0.06; 1.33 ؎ 0.13; 1.41 ؎ 0.07 mmol/L; P < 0.05). Phosphomonoesters, phosphodiesters, and liver aminotransferases did not differ between groups. HLVF was not different between those from the T2DM and mCON groups, but higher (P ‫؍‬ 0.002) than in those from the yCON group. T2DM had 13-fold higher iEGP than mCON (P < 0.05). Even after adjustment for HLVF, hepatic ATP and Pi related negatively to hepatic insulin sensitivity (iEGP) (r ‫؍‬ ؊0.665, P ‫؍‬ 0.010, r ‫؍‬ ؊0.680, P ‫؍‬ 0.007) but not to whole-body insulin sensitivity. Conclusion: These data suggest that impaired hepatic energy metabolism and insulin resistance could precede the development of steatosis in individuals with T2DM. (HEPATOLOGY

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“…Importantly, these studies demonstrated that hepatic necrosis occurred only when mitochondrial electron transport was inhibited [51,54]. Similarly, Diehl and colleagues demonstrated using 31 P NMR spectroscopy that recovery from hepatic ATP depletion is severely impaired in NASH patients [56] suggesting a NASH dependent bioenergetic defect. However, what was more revealing from this small pilot study was the observation that body mass index was inversely correlated with ATP recovery even in the healthy lean control subjects.…”

Section: Mitochondria Dysfunction In Fatty Liver Diseases -Bioenergetmentioning

confidence: 92%

“…This finding indicates that defects in energy conservation (i.e. mitochondrial dysfunction) may occur before fatty liver disease is present [56]. Studies have also shown that alcohol mediated liver damage accompanies defects in mitochondrial function and the inability to maintain hepatic ATP concentrations [57,58].…”

Section: Mitochondria Dysfunction In Fatty Liver Diseases -Bioenergetmentioning

confidence: 99%

Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases

Mantena

King

Andringa

et al. 2008

Free Radical Biology and Medicine

388

302

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Fatty liver disease associated with chronic alcohol consumption or obesity/type 2 diabetes has emerged as a serious public health problem. Steatosis, accumulation of triglyceride in hepatocytes, is now recognized as a critical "first-hit" in the pathogenesis of liver disease. It is proposed that steatosis "primes" the liver to progress to more severe liver pathologies when individuals are exposed to subsequent metabolic and/or environmental stressors or "second-hits". Genetic risk factors can also influence the susceptibility and severity of fatty liver disease. Furthermore, oxidative stress, disrupted nitric oxide (NO) signaling, and mitochondrial dysfunctional are proposed to be key molecular events that accelerate or worsen steatosis and initiate progression to steatohepatitis and fibrosis. This review article will discuss the following topics regarding the pathobiology and molecular mechanisms responsible for fatty liver disease: 1) the "two-hit" or "multi-hit" hypothesis; 2) the role of mitochondrial bioenergetic defects and oxidant stress; 3) interplay between NO and mitochondria in fatty liver disease; 4) genetic risk factors and oxidative stress responsive genes; and 5) the feasibility of antioxidants for treatment.

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Alterations in Liver ATP Homeostasis in Human Nonalcoholic Steatohepatitis

Cited by 451 publications

References 25 publications

Metabolomic‐based noninvasive serum test to diagnose nonalcoholic steatohepatitis: Results from discovery and validation cohorts

Metabolomic‐based noninvasive serum test to diagnose nonalcoholic steatohepatitis: Results from discovery and validation cohorts

Abnormal Hepatic Energy Homeostasis in Type 2 Diabetes†

Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases

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