Sex-Specific Protection Against Diet-Induced Non-Alcoholic Fatty Liver Disease in TRPV1 Null Mice

Abstract

ObjectivesTRPV1 channels have been linked to the development and progression of diabetes at multiple levels, including control of appetite and weight, regulation of pancreatic function, thermogenesis, metabolism and energy homeostasis. Despite this, little information is known regarding its role in liver homeostasis and nonalcoholic fatty liver disease (NAFLD).Methods and ResultsTo better understand the role of TRPV1 in liver metabolism, we explored the effects of a high fat/sugar diet (Western, 24-week regimen) in male and female wild type (WT) and TRPV1-null (V1KO) mice. Our data reveal that loss of the TRPV1 gene makes mice susceptible to diet-induced obesity and induces NAFLD. V1KO mice displayed gross phenotypic and gross morphological changes including insulin resistance, glucose intolerance, increased body mass and central adiposity on a western diet compared to WT counterparts. Western fed V1KO mice exhibited gross changes in liver morphology and size compared to western fed WT mice, which were supported with histological H&E and Oil Red O staining. Accompanying the liver changes, Western fed V1KO mice exhibited altered lipid profiles as demonstrated by elevated hepatic triglyceride, cholesterol and free fatty acid levels compared to western fed WT mice. Interestingly, female V1KO mice fed a western diet displayed significant protection against diet-induced obesity and the progression of NAFLD compared to their male counterparts. Taken together, these data suggest that loss of TRPV1 promotes fat accumulation, NAFLD development and changes in liver lipid profiles in male mice, the extent to which is less severe in female V1KO mice.ConclusionIn conclusion, TRPV1 may be a protective therapeutic target for the prevention of NAFLD development in diet-induced obesity.

The interaction of TRPV1 and lipids: Insights into lipid metabolism

“…In apolipoprotein E-deficient mice, evodiamine significantly reduced atherosclerosis, hyperlipidemia, and systemic inflammation and this beneficially therapeutic effect was not seen in ApoE −/− mice that lack TRPV1 ( Wei et al, 2013 ), suggesting that TRPV1 curbs the development of atherosclerosis. A similar observation was shown by Connell et al (2018) who showed that loss of TRPV1 gene in western-fed mice caused higher hepatic triglycerides, cholesterol and free fatty acid levels than wild type (WT) mice and this effect was more obvious in males than in females ( Connell et al, 2018 ). Similarly, Baskaran et al (2021) found that TRPV1 deficient mice developed metabolic dysfunction.…”

Association between Variants of the TRPV1 Gene and Body Composition in Sub-Saharan Africans

“…Decreased TRPV1 expression in mice has been found to protect against diet-induced obesity [ 78 ] and promotes oxygen consumption, fat oxidation, and locomotor activity [ 79 ]. In contrast, loss of the TRPV1 gene in Western-fed mice causes hyperlipidemia, and animals exhibit reduced locomotor activity with a more pronounced effect in males than in females [ 80 , 81 ]. TRPV1 agonists, such as vanilloids, capsaicin, and oxytocin, influence lipid metabolism, mainly by reducing lipid deposition.…”