Obesity is associated with changes in oxysterol metabolism and levels in mice liver, hypothalamus, adipose tissue and plasma

Abstract

Oxysterols are bioactive lipids derived from cholesterol that are linked to inflammatory processes. Because obesity and metabolic syndrome are characterized by inflammation and altered cholesterol metabolism, we sought to investigate the variations of oxysterol levels and their metabolic pathways induced by obesity in the liver, hypothalamus, adipose tissue and plasma. To this end, we used diet-induced and genetic (ob/ob and db/db) models of obesity. Among the oxysterols measured, we found that 4β-oxysterol levels were consistently decreased in the high-fat diet study, at different time-points, and in the ob/ob model. Overall, we did not find any correlation between cytochromes mRNA expression and variations of oxysterol levels. We also measured the levels of hepatic primary bile acids, in these three models and found similar profiles between HFD and ob/ob mice. However, although they are downstream metabolites of oxysterols, the variations in bile acid levels did not reflect the variations of their precursors. Our data show that, when considering oxysterol metabolism, the high-fat diet and ob/ob models are more closely related when compared to the db/db model. However, we were able to discriminate between lean and obese phenotypes based on liver oxysterol (4β-hydroxycholesterol, 27- hydroxycholesterol, 7-hydroxycholestenone) levels and enzyme (CYP3A11, CYP27A1, CYP7A1) expression.

Elevated 4β‐hydroxycholesterol/cholesterol ratio in anorexia nervosa patients

“…However, distorted 4βOHC levels could be caused by changes both in production and elimination, and 4βOHC is further metabolized via CYP7A1 and CYP27A1 . Reduced 4βOHC and elevated plasma 27OHC levels have been reported in an obese mouse model, which could indicate that obesity is associated with increased CYP27A1 activity and therefore increased elimination of 4βOHC . However, Ulvestad et al.…”

“…3 Reduced 4βOHC and elevated plasma 27OHC levels have been reported in an obese mouse model, which could indicate that obesity is associated with increased CYP27A1 activity and therefore increased elimination of 4βOHC. 24 However,…”

Dietary fat and gut microbiota interactions determine diet-induced obesity in mice

“…Recent studies revealed that changes in gut colonization in response to diet result in altered energy balance and contribute to obesity and metabolic disorders, such as diabetes. The need to better define the molecular mechanisms governed by diet–microbiota–host interactions has been addressed [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], in particular since studies on energy balance in germfree (GF) mice revealed conflicting results [13], [14]. Controversial findings may have their origin in the obesogenic diets used.…”

Liver x receptor alpha drives chemoresistance in response to side-chain hydroxycholesterols in triple negative breast cancer

“…Excitingly, these interventions could be tailored to the patient to offer an element of control to individuals who may otherwise seek lifestyle an dietary guidance from sources that have not been peer reviewed (Thorne et al, 2020). It of course remains to be determined if such strategies would be beneficial in improving survival rates via chemosensitization, but it is encouraging that extra-hepatic scOHC levels are modifiable by diet (Guillemot-Legris et al, 2016;Sozen et al, 2018) as well as circulating levels being highly responsive to statins (Dias et al, 2018). A meta-analysis of statin use in unstratified breast cancer patients has shown inhibition of cholesterol synthesis was associated with protection from relapse and death in the first 4 years post-diagnosis (Liu et al, 2017a), which interestingly, is the period of highest relapse risk for TNBC patients (Liedtke et al, 2008).…”