Inhibition of carnitine palymitoyltransferase1b induces cardiac hypertrophy and mortality in mice

Abstract

Recent reports suggest that short-term pharmacological Cpt1 inhibition improves skeletal muscle glucose tolerance and insulin sensitivity. While this appears promising for the treatment of diabetes these Cpt1 inhibitors are not specific to skeletal muscle and target multiple Cpt1 isoforms. To assess the effects of inhibiting the Cpt1b isoform we generated mice with a heart and skeletal muscle specific deletion of the Cpt1b, Cpt1bHM−/−. These mice seem to develop normally with similar bodyweights as control mice. However, by 15 weeks of age the Cpt1bHM−/− mice begin to die. The hearts of Cpt1bHM−/− mice were 4-times the size of controls. Cpt1bHM−/− mice were also subject to stress-induced seizures that accompanied an increased risk for premature mortality. Our data suggests that prolonged Cpt1b inhibition poses severe cardiac risk and emphasizes that attempts to improve insulin sensitivity by targeting Cpt1 with current inhibitors is not viable.

"Diabetes Mellitus: could the Inhibition of a Single Enzyme (CPT-1) Involved in the Beta-Oxidation Process Improve this Complex Disease?"

“…In addition, some negative aspects were already highlighted in previous studies such as steatosis [16] and apoptosis [17,18]; the latter aspect as to generate a new stream of research to anticancerogenic action due to CPT1 inhibition [19,20]. Moreover, other dangerous negative aspects of CPT blocking such as cardiac mitochondrial toxicity [21], cardiac hypertrophy [22,23] and mortality for prolonged inhibition [24] emerged in other studies; consider that diabetes is a chronic disease and as such should be treated, the continued blockade of the CPT may be contraindicated? In contrast, some evidence had emerged from other CPT inhibitors to ameliorate or not effect on cardiac performance as result of inhibition [11,24,25].…”

“…Moreover, other dangerous negative aspects of CPT blocking such as cardiac mitochondrial toxicity [21], cardiac hypertrophy [22,23] and mortality for prolonged inhibition [24] emerged in other studies; consider that diabetes is a chronic disease and as such should be treated, the continued blockade of the CPT may be contraindicated? In contrast, some evidence had emerged from other CPT inhibitors to ameliorate or not effect on cardiac performance as result of inhibition [11,24,25]. In addition, a recent report showed that a long-term increase in hepatic fatty acid oxidation leads to a beneficial effect in a mouse model of obesity and diabetes [26].…”

Fatty acid oxidation by the osteoblast is required for normal bone acquisition in a sex- and diet-dependent manner

“…Cpt1, which transfers fatty acyl groups from CoA to carnitine, is associated with the outer mitochondrial membrane and is the rate-limiting enzyme in fatty acid β-oxidation. However, this enzyme is encoded by 3 isoforms (Cpt-1a, Cpt-1b, and Cpt-1c) with overlapping tissue expression patterns (27)(28)(29)(30)(31) and the potential for functional compensation among isoforms in gene loss of function studies (32). Cpt2, which reverses the reaction catalyzed by Cpt1 after the shuttling of acylcarnitines by specific transporters into the mitochondrial matrix, is associated with the inner mitochondrial membrane and encoded by a single gene (30).…”

Impaired mitochondrial fat oxidation induces adaptive remodeling of muscle metabolism

“…Furthermore, Cpt1 inhibition is associated with both cardiac hypertrophy and hepatic steatosis (24)(25)(26). There have been attempts to inhibit the muscle isoform, Cpt1b (23), specifically; however, long-term risks of cardiac hypertrophy and mortality (27) suggest that pharmacological strategies must target specifically skeletal muscle.…”