Mitochondrial involvement in non-alcoholic steatohepatitis

Serviddio, Gaetano; Sastre, Juan; Bellanti, Francesco; Viña, José; Vendemiale, Gianluigi; Altomare, Emanuele

doi:10.1016/j.mam.2007.09.014

Cited by 98 publications

(85 citation statements)

References 110 publications

(123 reference statements)

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“…Octanoic acid is a medium-chain fatty acid that enters the mitochondrial matrix independently of carnitine palmitoyltransferase 1 (CPT1) and rapidly stimulates mitochondrial β-oxidation and gluconeogenesis (19). Consistent with the observation of hyperglycemia in standard chow diet-fed HMGCS2 ASO-treated mice (Supplemental Figure 2G), we found that basal gluconeogenesis from pyruvate in the absence of octanoic acid was increased in the livers of ketogenesis-insufficient animals (15.2 ± 2.1% 13 C enrichment of glucose vs. 9.0 ± 1.0% in controls, n = 7-8/group, P = 0.015; Figure 6A). Because total hepatic glucose concentrations did not differ between groups (Figure 6B), the increased enrichment reflects increased production from pyruvate.…”

Section: 8supporting

confidence: 82%

“…livers of these mice exhibit impaired ketogenesis, i.e., are ketogenesis insufficient (Supplemental Figure 1F). Despite exhibiting marked ketogenic impairment, we observed that HMGCS2 ASOtreated mice fed a standard low-fat chow diet did not differ in body weight, body composition, or food intake compared with control of the 13 C-label using 13 C-edited proton NMR profiling (31-34) revealed markedly blunted incorporation of the label into βOHB in HMGCS2 ASO-treated mice in both the fed and overnight-fasted states. These results confirm that HMGCS2 is required for effective derivation of ketone bodies from fatty acids and indicate that + and (E) SMA + cells in cryosections of liver from ASO-treated mice fed an HFD for 8 weeks.…”

Section: Resultsmentioning

confidence: 77%

“…However, decreased glycemia in ketogenesis-insufficient mice was not entirely attributable to decreased caloric intake, because the capacity to support de novo glucose production from [ 13 C]pyruvate was decreased 4-fold in perfused livers of HFD-fed HMGCS2 ASO-treated mice (1.8 ± 0.3% vs. 7.3 ± 1.1% fractional enrichment as [ 13 C]glucose in controls, P = 0.0009, n = 4-5/group; Figure 3E). While the total hepatic glucose pool was expanded in perfused livers of HFD-fed HMGCS2 ASO-treated mice ( Figure 3F), de novo 13 C-labeling of glucose from [ 13 C]pyruvate was markedly diminished in HFD-fed HMGCS2 ASO-treated livers (3.9 ± 1.7 pmol vs. 10.4 ± 0.9 pmol […”

Section: 8mentioning

confidence: 99%

“…Given the alterations we identified in mRNAs of DNL mediators, metabolites in the fatty acid elongation pathway were of particular interest. Thus, we searched all features of 13 C-labeled in hepatic mitochondria isolated from ketogenesis-insufficient animals (data not shown), oxygen consumption using pyruvate alone was markedly impaired: respiratory rates were diminished 31% in state 2 (basal proton leak), 62% in state 3 (ADP-stimulated), 49% in state 4 (ATP synthase-inhibited), and 65% during uncoupled (maximal) respiration ( Figure 4A). These results suggested relatively impaired pyruvate oxidation in ketogenesis-insufficient mice.…”

Section: 8mentioning

confidence: 99%

“…Nonetheless, most investigators agree that abnormalities of mitochondrial metabolism occur in and contribute to NAFLD (reviewed in refs. [13][14][15].…”

Section: Introductionmentioning

confidence: 99%

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Ketogenesis prevents diet-induced fatty liver injury and hyperglycemia

et al. 2014

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R e s e a R c h a R t i c l e5 1Ketogenic insufficiency causes hepatic inflammation, injury, and altered glucose metabolism in the setting of carbohydrate-replete overnutrition. To determine the effects of ketogenic insufficiency in the context of overnutrition, mice previously receiving ASOs for 2 weeks while on a standard low-fat chow diet were then maintained for 8 weeks on a 60% high-fat diet (HFD) commonly used to induce hyperglycemia, hepatic steatosis, and inflammation in WT mice. HMGCS2 immunoblots indicated that hepatic HMGCS2 mice (Supplemental Figure 2, A-C). HMGCS2 ASO-treated mice also exhibited normal serum free fatty acid (FFA) and TAG concentrations and a normal physiologic distribution of residual βOHB and AcAc (Supplemental Figure 2, D-F). Interestingly, HMGCS2 ASO-treated mice displayed mild, but very consistently elevated, blood glucose concentrations (160.9 ± 3.2 mg/dl vs. 145.0 ± 3.4 mg/dl in controls, n = 28-36/group, P = 0.0013), without changes in serum insulin concentrations (Supplemental Figure 2, G and H). C]pyruvate, quantified by NMR profiling of perfused liver extracts from ASO-treated mice fed a 60% HFD for 8 weeks. n = 4-5/group. *P < 0.05, **P < 0.01, ***P < 0.001 by Student's t test.

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Section: 8supporting

confidence: 82%

Section: Resultsmentioning

confidence: 77%

Section: 8mentioning

confidence: 99%

Section: 8mentioning

confidence: 99%

“…Nonetheless, most investigators agree that abnormalities of mitochondrial metabolism occur in and contribute to NAFLD (reviewed in refs. [13][14][15].…”

Section: Introductionmentioning

confidence: 99%

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Ketogenesis prevents diet-induced fatty liver injury and hyperglycemia

et al. 2014

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Lactic acid in cancer and mitochondrial disease

Steliou

Perrine

Faller

2009

Drug Development Research

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Cancer and the mitochondrial diseases are disparate disorders that have in common a failure of normal cellular respiratory activity in disease-affected tissues. In mitochondrial diseases, the impairment in the mitochondria is often the result of abnormalities in their mtDNA, whereas in cancerous cells, the altered respiration is driven by the Warburg effect. The oxidation of glucose (as pyruvate in the mitochondria) is inhibited and energy production relies on cytoplasmic glycolysis. This suppressed mitochondrial activity confers in tumor cells a state of resistance to apoptosis and, in mitochondrial diseases like mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), the altered respiration leads to lactic acidosis. Driving glucose to its complete oxidation inside the mitochondria has potential in cancer therapy to reconstitute apoptotic competence in tumor cells and, in mitochondrial disease, to treat lactic acidosis. This minireview investigates the development of small molecule agents for suppressing the Warburg effect in cancer therapy and lactic acidosis in mitochondrial disease. Drug Dev Res 70 : 499-511, 2009.

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Unveiling global research trends and hotspots on mitochondria in NAFLD from 2000 to 2023: A bibliometric analysis

Hu,

Chen,

Zhou

et al. 2024

Immunity Inflam & Disease

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BackgroundNonalcoholic fatty liver disease (NAFLD) has garnered significant attention in the past decade as a prevalent chronic liver condition. Despite a growing body of evidence implicating mitochondria in NAFLD development, comprehensive bibliometric analyses within this research domain are scarce. This study aims to provide a thorough overview of the knowledge framework and key research areas related to mitochondria in the context of NAFLD, utilizing bibliometric techniques.MethodsA comprehensive search of publications on mitochondria in NAFLD from 2000 to 2023 was conducted using the Web of Science Core Collection database. VOSviewers, CiteSpace, and the R package “bibliometrix” were employed for a precise assessment of the literature.ResultsExamining 2530 articles from 77 countries, primarily led by the United States and China, revealed a consistent increase in publications on mitochondria's role in NAFLD. Leading research institutions include the University of Coimbra, the University of Missouri, the Chinese Academy of Sciences, Fudan University, and Shanghai Jiao Tong University. Notably, the International Journal of Molecular Sciences emerged as the most popular journal, and Hepatology was the most frequently cited. With contributions from 14,543 authors, Michael Roden published the highest number of papers, and A. J. Samyal was the most frequently cocited author. Key focus areas include investigating mitochondrial mechanisms impacting NAFLD and developing therapeutic strategies targeting mitochondria. Emerging research hotspots are associated with keywords such as “inflammation,” “mitochondrial dysfunction,” “autophagy,” “obesity,” and “insulin resistance.”ConclusionThis study, the first comprehensive bibliometric analysis, synthesizes research trends and advancements in the role of mitochondria in NAFLD. Insights derived from this analysis illuminate current frontiers and emerging areas of interest, providing a valuable reference for scholars dedicated to mitochondrial studies.

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Mitochondrial involvement in non-alcoholic steatohepatitis

Cited by 98 publications

References 110 publications

Ketogenesis prevents diet-induced fatty liver injury and hyperglycemia

Ketogenesis prevents diet-induced fatty liver injury and hyperglycemia

Lactic acid in cancer and mitochondrial disease

Unveiling global research trends and hotspots on mitochondria in NAFLD from 2000 to 2023: A bibliometric analysis

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