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    • br Liver specific AHR deficiency

    2024-04-01


    Liver-specific AHR deficiency and energy balance In contrast to the amelioration of hepatic steatosis by global AHR deficiency, targeted knockout of Ahr in hepatocytes exacerbated it in B6 mice fed on a high-fat diet, without interfering with body weight gain [21]. This appeared to result from augmented expression of genes involved in de novo lipogenesis such as Srebp1c, Scd1, Acc1 and Gpat1, whereas those related to fatty Kenpaullone synthesis uptake, β-oxidation or gluconeogenesis were not differentially affected from control mice on the same diet. High-fat diet-induced hepatic inflammation was also aggravated in knockout mice, coinciding with reduced induction of Socs3, the gene for a negative regulator of STAT3 (a mediator of cytokine signaling [22]). Rescue of hepatic Socs3 expression largely reversed the deleterious effects of hepatic AHR deficiency; the authors further demonstrated Socs3 to be transcriptionally regulated by the AHR [21]. In two other studies using B6 mice on regular chow, both cholesterol and fatty acid biosynthesis in the liver were enhanced by hepatocyte-specific ablation of AHR and repressed by AHR activation (instigated by β-naphtoflavone) through coordinated transcriptional regulation; the AHR proved to exert these effects by a non-canonical pathway [23,24]. These findings are illustrated in Figure 2.
    Constitutively active hepatic AHR and energy balance In FVB mice fed regular chow, the reverse setting, expression of a constitutively active AHR in the liver (and intestine), also resulted in accumulation of lipids in the liver [25]. While hepatic trigycerides were increased compared with the wildtype control, hepatic cholesterol and plasma triglyceride levels were not. Both body and fat mass decreased in the transgenics, whereas lean body mass was elevated. In the liver, the expression of Ppara and Acox1 was reduced but that of Cd36 and two fatty acid transporters, Fatp1 and Fatp2, augmented, suggesting enhanced uptake of fatty acids in the face of their impaired utilization. Moreover, oxidative stress was aggravated [25].
    Adipose tissue-specific AHR deficiency and energy balance The impact of organ-specific AHR deficiency has also been tested for the adipose tissue. Compared with wildtype controls, transgenic mice on B6-FVB background, devoid of AHR in mature white adipocytes and with reduced (by 35%) Ahr expression in the brown adipose tissue, exhibited increased relative fat mass and decreased relative lean mass, without any difference in body weight, on standard mouse diet [26]. No effect was found on glucose tolerance but insulin sensitivity was slightly enhanced. When fed on a high-fat diet, the AHR-deficient mice gained weight more rapidly than their controls from week 5 on due to enhanced subcutaneous fat accumulation, but both glucose tolerance and insulin sensitivity remained unchanged (as measured 4 weeks after an induced weight loss period following 12-week feeding of the high-fat diet). Relevant to these findings, aNF dose-dependently promoted triglyceride accumulation and IL-6 secretion in mature murine 3T3-L1 adipocytes in vitro[27]. The reported consequences of adipose tissue-specific reduction in AHR activity on factors related to energy homeostasis are summarized in Figure 3.
    Is AHR a protein sensor? Based on the evidence available at present, AHR signaling is not indispensable for the regulation of energy homeostasis in the body but rather a modulator whose involvement mainly requires high energy intake to become manifest. At the whole organism level, the predominant effect appears to be curtailment of resting energy expenditure in extrahepatic tissues, particularly in brown adipose tissue and skeletal muscle, although this has yet to be verified by functional measurements. These two are crucial tissues for adaptive thermogenesis instigated by exposure to cold or excess dietary energy [28]. In brown adipose tissue, the protein product of Ucp-1 enables protons to bypass ATP synthase in mitochondria, thus generating heat. It is mainly regulated by the sympathetic nervous system, the three PPARs and PGC-1α [29]. In skeletal muscle, the molecular mechanisms of non-shivering thermogenesis are still poorly defined, but major mediators of fatty acid oxidation and upregulation of energy expenditure in that tissue are PPARδ and PGC-1α [11,30]. Because in mice harboring adipose tissue-specific AHR deficiency body weight gain was accelerated on high-fat diet vs. wildtype animals on the same diet, global AHR ablation might act at a higher regulatory level than the brown adipose tissue itself, i.e. the brain or the sympathetic nervous system (see Figure 4). However, it is also possible that the reduction in AHR activity in the brown adipose tissue was too small to effectively trigger heat generation.