Abstract
In vertebrates, the initial step in heme biosynthesis is the production of 5-aminolevulinic acid (ALA) by ALA synthase (ALAS). ALA formation is believed to be the rate-limiting step for cellular heme production. Recently, several cohort studies have demonstrated the potential of ALA as a treatment for individuals with prediabetes and type-2 diabetes mellitus. These studies imply that a mechanism exists by which ALA or heme can control glucose metabolism. The ALAS1 gene encodes a ubiquitously expressed isozyme. Mice heterozygous null for ALAS1 (A1+/-s) experience impaired glucose tolerance (IGT) and insulin resistance (IR) beyond 20-weeks of age (aged A1+/-s). IGT and IR were remedied in aged A1+/-s by the oral administration of ALA for 1 week. However, the positive effect of ALA proved to be reversible and was lost upon termination of ALA administration. In the skeletal muscle of aged A1+/-s an attenuation of mitochondrial function is observed, coinciding with IGT and IR. Oral administration of ALA for 1-week brought about only a partial improvement in mitochondrial activity however, a 6-week period of ALA treatment was sufficient to remedy mitochondrial function. Studies on differentiated C2C12 myocytes indicate that the impairment of glucose metabolism is a cell autonomous effect and that ALA deficiency ultimately leads to heme depletion. This sequela is evidenced by a reduction of glucose uptake in C2C12 cells following the knockdown of ALAS1 or the inhibition of heme biosynthesis by succinylacetone. Our data provide in vivo proof that ALA deficiency attenuates mitochondrial function, and causes IGT and IR in an age-dependent manner. The data reveals an unexpected metabolic link between heme and glucose that is relevant to the pathogenesis of IGT/IR.
Highlights
We demonstrate that ALAS1 heterozygous mice (A1+/-s) develop impaired glucose tolerance, insulin resistance and an attenuation of mitochondrial function in skeletal muscle beyond 15 wks of age, correlating with the reduced expression of ALAS1 (Fig 2B, 2C, 2F and 2G)
This study provides the first evidence that an in vivo deficiency of aminolevulinic acid (ALA) can lead to impaired glucose tolerance and insulin resistance, and reveals an unexpected link between heme and glucose metabolism
Our data further indicate that the impairment of glucose metabolism caused by ALA deficiency occurs in a cell-autonomous manner
Summary
5-aminolevulinic acid (ALA) production is the first step in heme biosynthesis, which in higher vertebrates is a function of the ALA synthase (ALAS) enzyme. It has been observed that heme deficiency can interrupt the assembly of mitochondrial Complex IV in human fibroblasts [11] It remains unclear whether heme deficiency in vivo leads to mitochondrial dysfunction. Two recent cohort studies in Japan [12] and Hawaii [13], suggest that oral ALA can protect against mild hyperglycemia and help prevent type-2 diabetes mellitus (T2DM) These studies strongly suggest that heme or ALA is associated with glucose metabolism in vivo. Heme-sensing by Rev-erbα acts to regulate glucose homeostasis (by suppressing glucose output and the expression of gluconeogenic genes such as glucose 6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK)), to control circadian rhythms (by regulation of the Bmal gene) and to modulate energy metabolism (by, inter alia, the supply of heme for mitochondrial respiration). In contrast to the effect on IGT and IR, only a partial recovery in mitochondrial function was achieved by a 1 wk treatment of ALA and instead, a prolonged treatment period of 6 wks was required to elicit a positive effect
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