Metabolic and Cardiac Manifestations in a Mouse Model of Genetic Mitochondrial Hepatopathy Without Obesity: Evidence for a Sexual Dimorphism
Bibliographic record
Abstract
Objective In non‐alcoholic fatty liver disease (NAFLD), liver mitochondrial dysfunction plays an important role in the development of cardiac abnormalities independent of obesity per se . However, the mechanisms underlying the development of these abnormalities, and whether these are affected by sex remain unclear. In the present study, we sought to address this question using a mouse model of hepatic mitochondrial deficiency caused by loss of Lrpprc (H‐ Lrpprc ‐/‐ ) as these mice develop microvesicular steatosis and a NAFLD lipidomic‐like profile without obesity. Hypothesis Our working hypothesis is that metabolic defects in the liver would trigger metabolic and functional abnormalities in the heart in a sex‐dependent manner. Methods Detailed phenotyping experiments were performed in male and female H‐ Lrpprc ‐/‐ mice and their controls at 14 weeks of age. Glucose metabolism was monitored by blood glucose as well as insulin, and glucose tolerance tests (ITT, OGTT). Cardiac manifestations were studied using molecular (qPCR), lipidomic (mass spectrometry) and functional (oximetry on isolated mitochondria, intraventricular pressures by Millar probe) analyses. Results Genetic inactivation of Lrpprc resulted in an >60% reduction of LRPPRC protein content in both males and females, which resulted in comparable structural liver abnormalities. In contrast, the resulting metabolic and cardiac functional changes displayed a marked sexual dimorphism. Lrpprc deficiency in the liver was associated with fasting hypoglycemia and increased insulin sensitivity in both sexes, but more so in males. Lrpprc deficiency was also associated with a remodeling of specific markers of mitochondrial function exclusively in the female myocardium. This included 1) reduced expression of gene markers for mitochondrial biogenesis ( Tfam ), fusion ( Mfn1‐2 ), and fatty acid (FA) utilization and oxidation (Pparα, Cd36 , Cpt1b , Cpt2 , Vlcad , Lcad , Mcad ), 2) impairment of FA‐dependent mitochondrial respiration, and 3) increased cardiac triglyceride levels. Paradoxically, cardiac function was preserved in females, while males displayed mild diastolic dysfunction as evidenced by increased early and late diastolic pressures (0.29 and 2.39 fold vs. male wild type respectively) amongst other parameters. Conclusion Collectively, these results indicate that metabolic defects in the liver can result in significant sex‐dependent abnormalities that affect both the mitochondrial/metabolic phenotype and contractile function independent of obesity. This experimental model may prove useful to better understand the mechanisms underlying the sex‐related variability in the progression of lean NAFLD in humans.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.002 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".