Non-alcoholic fatty liver disease (NAFLD) is now the most common chronic liver disease, and the fastest-growing reason for liver transplantation. It is estimated that more than half of patients with type 2 diabetes (T2D) have NAFLD, and even patients with type 1 diabetes have higher risk of developing fatty liver than people without diabetes. There are currently no drugs approved to treat NAFLD. Even more vexing, novel therapeutics for T2D that increase liver insulin sensitivity generally increase fat deposition in the liver, creating a vicious cycle that paradoxically worsens the liver disease.
Now, diabetes investigator Utpal Pajvani, MD, PhD, and his team of researchers at the Naomi Berrie Diabetes Center, led by KyeongJin Kim, PhD, have discovered that a simple protein, originally thought to do one job, has the capability of doing something completely different—and quite extraordinary. “We found, for the first time, a pathway that prevents insulin or insulin sensitizing therapy from causing fatty liver, without getting rid of the favorable effects of insulin to reduce blood sugar,” said Dr. Pajvani, an Assistant Professor of Medicine at Columbia University In a paper released in the January 2016 issue of Nature Communications.
Drs. Kim and Pajvani document the secret life of a protein called Raptor that exists within a protein complex called mTORC1 which is involved in everything from cell growth and cell differentiation to cell usage of glucose or lipids. “mTORC1 is one of the most-studied biological pathways, since it has so many functions, and has been implicated not only in the development of diabetes and fatty liver disease, but also cancer,” said Dr. Pajvani.
Raptor has long been known to be the regulatory component of mTORC1’s function to phosphorylate other proteins, but Dr. Pajvani’s group reports for the first time that Raptor not only exists independently from mTORC1, but has the capacity in its free state to reverse fatty liver in mice by stabilizing another protein called PHLPP2, which in turn turns off insulin signaling. Aging or obesity normally cause PHLPP2 to degrade, leaving in its wake “a chronic, smoldering insulin signaling that results in fatty liver. Free Raptor, through protecting PHLPP2 from degradation, turns off the insulin signaling.”
While the nomenclature of the protein complex is difficult to the uninitiated (his paper is entitled “mTORC1-independent Raptor prevents hepatic steatosis by stabilizing PHLPP2”) Dr. Pajvani’s explanation of his discovery as it played out in laboratory mice, is clear, concise and compelling.
“As it turns out, young, healthy mice, (and we assume, young, healthy people) have a lot of this free Raptor. As mice age or get fat, free Raptor disappears. When free Raptor disappears, mice get fatty liver. If you give them back free Raptor, fatty liver goes away but leaves insulin’s ability to lower blood sugar intact.”
Dr. Pajvani’s work is big news for the other scientists who study insulin resistance, diabetes and other metabolic disorders, but may have stronger impact still in far-flung domains such as cancer biology. This same pathway is targeted by cancer researchers and immunologists, and mTORC1 inhibitors are already in clinical use as chemotherapy for cancer patients and as an immunosuppressant for organ transplant patients. “The role of free Raptor that we discovered is not likely to be limited to hepatic lipid metabolism to prevent age and obesity induced fatty liver,” said Dr. Pajvani. “If we can figure out what frees Raptor from mTOR, we may have accidentally discovered a better means to modulate this very important pathway in order to design a more effective cancer or immunosuppressant drug.” But, we’re some time away from this, he cautions: “All we have are genetic mouse models – we have to prove the relevance of this free Raptor-PHLPP2 axis in people, which may give impetus for pharmaceutical companies to develop a drug to do the same.”
Dr. Pajvani’s research focuses on the role of developmental pathways in the regulation of diabetes and related metabolic complications, such as fatty liver disease. Dr. Pajvani, 40, is also an endocrinologist who sees patients at the Naomi Berrie Diabetes Center.