Apolipoprotein CIII in the pathophysiology of diabetes mellitus

It has previously been shown that high levels of apolipoprotein CIII (apoCIII) are related to both type-1 (T1D) and type-2 diabetes (T2D). In this thesis, mechanisms whereby apoCIII affects diet- and genetically-induced obesity and metabolic derangements, and the role of the environment and apoCIII in the development of T1D, have been studied.

In C57BL6/j (B6) mice fed a high-fat diet (HFD), preventing or reversing the increase in apoCIII with antisense oligonucleotides (ASO), resulted in the activation of lipases, and enhanced hepatic clearance and catabolism of circulating lipids. Lipid metabolism in the liver shifted towards ketogenesis and there was a reduction in de novo lipogenesis and gluconeogenesis. The ketone bodies were used for energy production in the brown adipose tissue (BAT). In white adipose tissue (WAT) there was reduced inflammation and increased expression of genes related to thermogenesis. Lowering apoCIII in HFD-fed mice promoted a normal insulin sensitivity and glucose homeostasis and counteracted the metabolic phenotype.

Even in obese and diabetic ob/ob and db/db mice, which lack leptin signaling, lowering of apoCIII with ASO twice per week improved glucose metabolism and insulin sensitivity, albeit to a lesser extent in the db/db mice. The ASO-treated mice had a reduced food intake and cessation of body weight gain. This was related to a partial recovery of hypothalamic insulin sensitivity with decreased expression of the orexigenic genes Npy and Agrp, and increased expression of the anorexigenic genes Pomc and Cart.

A small-interfering RNA (siRNA) mix, consisting of two mouse-specific siRNAs against apoCIII, was tested in ob/ob mice. The metabolic improvements were comparable to those obtained when ASO was used. However, the siRNA mix was more potent and had a longer duration than ASO, so the treatment was given every second week instead of twice per week.

The BioBreeding (BB) rat model, in which the diabetes-prone (DPBB) rats develop a human-like T1D when they are around 60 days old, was used to investigate the role of the environment and apoCIII in the development of T1D. Islets from DPBB or diabetes-resistant (DRBB) rats were transplanted into the anterior chamber of the eye (ACE) of 25 days-old DP or DR recipients. Five weeks after transplantation DR islets in the ACE of DP rats had a changed morphology, loss of functional vascular network, increased vascular leakage and infiltration of phagocytes, as compared to DP islets in DR recipients. This shows that a prediabetic milieu decides the fate of the islets. There was an increase in apoCIII in prediabetic islets and when DP islets were transplanted into the ACE of DP rats treated with siRNA against rat apoCIII, there was a delay in the onset of diabetes.

All these data, together with previous results, support that apoCIII has a role in the development of T1D and obesity-induced T2D.

List of scientific papers

I. Valladolid-Acebes I, Åvall K, Recio-López P, Moruzzi N, Bryzgalova G, Björnholm M, Krook A, Alonso EF, Ericsson M, Landfors F, Nilsson SK, Berggren PO, Juntti-Berggren L. 2021. Lowering apolipoprotein CIII protects against high-fat diet-induced metabolic derangements. Science Advances. 7(11): eabc2931.
https://doi.org/10.1126/sciadv.abc2931

II. Recio-López P, Valladolid-Acebes I, Berggren PO, Juntti-Berggren L. 2021. Apolipoprotein CIII Reduction Protects White Adipose Tissues against Obesity-Induced Inflammation and Insulin Resistance in Mice. International Journal of Molecular Sciences. 23(1): 62.
https://doi.org/10.3390/ijms23010062

III. Valladolid-Acebes I, Recio-López P, Berggren PO, Juntti-Berggren L. Apolipoprotein CIII interferes with the hypothalamic circuitry controlling hunger and satiety in obese and diabetic mice. [Manuscript]

IV. Recio-López P, Valladolid-Acebes I, Hadwiger P, Hossbach M, Krampert M, Prata C, Berggren PO, Juntti-Berggren L. 2022. Treatment of the metabolic syndrome by siRNA targeting apolipoprotein CIII. Biofactors. 49(1): 153-172.
https://doi.org/10.1002/biof.1885

V. Recio-López P, Valladolid-Acebes I, Berggren PO, Juntti-Berggren L. The fate of the pancreatic islet is decided by its environment. [Manuscript]