Molecular characterization of hepatocarcinogenesis using mouse models

Hepatocellular carcinoma (HCC) is a deadly disease, often unnoticed until the late stages, when treatment options become limited. Thus, there is a crucial need to identify biomarkers for early detection of developing HCC, as well as molecular pathways that would be amenable to therapeutic intervention. Although analysis of human HCC tissues and serum components may serve these purposes, inability of early detection also precludes possibilities of identification of biomarkers or pathways that are sequentially perturbed at earlier phases of disease progression. We have therefore explored the option of utilizing mouse models to understand in a systematic and longitudinal manner the molecular pathways that are progressively deregulated by various etiological factors in contributing to HCC formation, and we report the initial findings in characterizing their validity. Hepatitis B surface antigen transgenic mice, which had been exposed to aflatoxin B1 at various stages in life, were used as a hepatitis model. Our findings confirm a synergistic effect of both these etiological factors, with a gender bias towards males for HCC predisposition. Time-based aflatoxin B1 treatment also demonstrated the requirement of non-quiescent liver for effective transformation. Tumors from these models with various etiologies resemble human HCCs histologically and at the molecular level. Extensive molecular characterization revealed the presence of an 11-gene HCC-expression signature that was able to discern transformed human hepatocytes from primary cells, regardless of etiology, and from other cancer types. Moreover, distinct molecular pathways appear to be deregulated by various etiological agents en route to formation of HCCs, in which common pathways converge, highlighting the existence of etiology-specific as well as common HCC-specific molecular perturbations. This study therefore highlights the utility of these mouse models, which provide a rich resource for the longitudinal analysis of molecular changes and biomarkers associated with HCC that could be exploited further for therapeutic targeting

A 12-week aerobic exercise intervention results in improved metabolic function and lower adipose tissue and ectopic fat in high-fat diet fed rats

10.1042/BSR20201707BIOSCIENCE REPORTS41

Clinical and imaging features of women with polygenic partial lipodystrophy: a case series

Abstract Background Familial partial lipodystrophy (FPLD) is an inherited disorder of white adipose tissue that causes premature cardiometabolic disease. There is no clear diagnostic criteria for FPLD, and this may explain the under-detection of this condition. Aim This pilot study aimed to describe the clinical features of women with FPLD and to explore the value of adipose tissue measurements that could be useful in diagnosis. Methods In 8 women with FPLD and 4 controls, skinfold measurements, DXA and whole-body MRI were undertaken. Results Whole genome sequencing was negative for monogenic metabolic causes, but polygenic scores for partial lipodystrophy were elevated in keeping with FPLD type 1. The mean age of diagnosis of DM was 31 years in the FPLD group. Compared with controls, the FPLD group had increased HOMA-IR (10.3 vs 2.9, p = 0.028) and lower mean thigh skinfold thickness (19.5 mm vs 48.2 mm, p = 0.008). The FPLD group had lower percentage of leg fat and an increased ratio of trunk to leg fat percentage on DXA. By MRI, the FPLD group had decreased subcutaneous adipose tissue (SAT) volume in the femoral and calf regions (p < 0.01); abdominal SAT, visceral adipose tissue, and femoral and calf muscle volumes were not different from controls. Conclusion Women with FPLD1 in Singapore have significant loss of adipose but not muscle tissue in lower limbs and have early onset of diabetes. Reduced thigh skinfold, and increased ratio of trunk to leg fat percentage on DXA are potentially clinically useful markers to identify FPLD1

Biochemical and body weight measurements of chow diet and HFD fed rats.

<p>The blood plasma cholesterol, triglycerides, glucose, insulin and body weight were significantly (<i>P</i><0.05).</p><p>* higher in HFD fed rats.</p

OGTT measurements.

<p>Time course of oral glucose tolerance test measurements from (A) plasma glucose and (B) plasma insulin for chow diet and HFD fed rats.</p

Saturated and unsaturated triglycerides by LC-MS.

<p>Concentrations of saturated and unsaturated TGs in HFD and chow diet fed rats estimated by LC-MS at 24 weeks. Triglycerides C50∶2, C50∶1, C52∶3, C52∶2 and C52∶1 were found to be most abundant (>100 nmol/ml) and significantly higher in HFD fed rats compared to chow diet fed rats. Concentrations of other TGs were less than 100 nmol/ml but significantly higher in HFD rats.</p

Liver fat and unsaturation indices estimated by <i>in vivo</i> MRS.

<p>Estimation of (A) liver fat (%) and (B) unsaturation indices by <i>in vivo</i> MRS from chow diet and high fat diet fed animals at the 12^th, 18^th and 24^th weeks. Liver fat content was significantly (<i>P</i><0.001) higher in HFD fed rats and unsaturation indices were significantly (<i>P</i><0.005) higher in chow diet fed rats for all age groups.</p

Triglycerides and unsaturation indices estimated from LC-MS.

<p>Estimation of (A) total triglycerides (B) unsaturation indices (by considering unsaturated FAs with n≥1 and (C) unsaturation indices (by considering unsaturated FAs with n>3) at 24 weeks in high fat diet and chow diet fed rats.</p

Effect of Exercise and Calorie Restriction on Tissue Acylcarnitines, Tissue Desaturase Indices, and Fat Accumulation in Diet-Induced Obese Rats.

Both exercise and calorie restriction interventions have been recommended for inducing weight-loss in obese states. However, there is conflicting evidence on their relative benefits for metabolic health and insulin sensitivity. This study seeks to evaluate the differential effects of the two interventions on fat mobilization, fat metabolism, and insulin sensitivity in diet-induced obese animal models. After 4 months of ad libitum high fat diet feeding, 35 male Fischer F344 rats were grouped (n = 7 per cohort) into sedentary control (CON), exercise once a day (EX1), exercise twice a day (EX2), 15% calorie restriction (CR1) and 30% calorie restriction (CR2) cohorts. Interventions were carried out over a 4-week period. We found elevated hepatic and muscle long chain acylcarnitines with both exercise and calorie restriction, and a positive association between hepatic long chain acylcarnitines and insulin sensitivity in the pooled cohort. Our result suggests that long chain acylcarnitines may not indicate incomplete fat oxidation in weight loss interventions. Calorie restriction was found to be more effective than exercise in reducing body weight. Exercise, on the other hand, was more effective in reducing adipose depots and muscle triglycerides, favorably altering muscle/liver desaturase activity and improving insulin sensitivity