While everyone’s familiar with the liver’s detoxifying functions (especially after a night of friendly drinking), most people are less familiar with the role of the liver as a regulator of “fuel” molecules in the blood: the liver stores and synthesizes glucose as needed, as well as being responsible for clearing excess cholesterol/fats from the body which are received as HDL (“good cholesterol”) and excreted into the intestines as bile. While the liver is generally considered one of the more resistant organs to aging, there are important changes in its structure during aging that result in overall declined function in the elderly, and because of the organ’s central role in controlling blood metabolism, these changes can have whole-body effects. Accordingly, dysfunctions in the liver have been investigated in aging-related metabolic diseases (type II diabetes, for example), cardiovascular disease, and chronic kidney disease.
Below are two studies that focus on understanding the role of the liver in metabolic diseases as well as interventions aimed at improving liver function in disease.
Recent research in obesity has focused on levels of branched-chain amino acids (BCAAs: leucine, isoleucine, and valine) as both a marker for people at risk for obesity/diabetes and as a contributor to disease; obese patients and those at risk of diabetes have elevated concentrations of BCAAs (and their breakdown products) in their blood, and BCAAs supplemented in diets given to mice cause mice to become insulin resistant. However, the reason for altered BCAA levels has been mysterious, which is an roadblock for developing strategies to treat this metabolic problem.
New insight into this phenomenon comes from the Buettner group at the Icahn School of Medicine, who used the euglycemic clamp technique (an IV technique which maintains insulin at a set level in blood) in rats to investigate the relationship between insulin levels and blood levels of BCAAs. They found that higher levels of insulin decreased BCAA concentrations, and that the opposite effect could be caused by blocking glucose uptake in the brain by a pharmacological agent, suggesting that there was a brain module responding to insulin that goes awry in metabolic diseases. They further tracked down the brain region involved by infusing insulin directly into the mediobasal hypothalamus (MBH, a region known to regulate food intake and energy balance), and observing that this was alone able to regulate the levels of BCAAs in blood. Since the brain is not known to directly control blood metabolite levels, the authors looked in other tissues (muscle, liver, etc) that express the enzyme necessary to metabolize BCAAs and found that the action of insulin in the brain (either by directly infusing insulin, or using mice lacking insulin receptors in the brain) and found that insulin action on the hypothalamus regulated the activity of the main enzyme that breaks down BCAAs in the liver.
Most interestingly for human health, the authors further observed that a high-fat diet fed to primates impaired insulin signaling in the hypothalamus and blocked liver activity of BCAA catabolic enzymes, suggesting that insulin resistance (particularly in the brain) is important for generating the blood abnormalities seen in obese/type-II-diabetic patients. This finding implies that BCAAs may be a good tracker for measuring the progression/treatment of insulin resistance in patients, and suggests that therapies directly targeting insulin signaling in the hypothalamus may hold promise for alleviating the obesity epidemic.
Fat-induced liver injury (“non-alcoholic fatty liver disease” or NAFLD) due to a high-fat diet is a significant cause of chronic disease in the western world; while obviously causing decreased liver function, it also increases the risk of type-2 diabetes and kidney failure. Drug targets to treat this type of disease would be useful, but without knowing what genes predispose people to this kind of liver damage, it’s been difficult for researchers to formulate treatments.
Using a difficult genetic technique (antisense oligonucleotides) to remove the function of a little-studied metabolic gene (HMGS2) in mice, researchers at Washington University in St. Louis determined that a metabolic process well-known to members of the fitness community by which our mitochondria use fat to make glucose—“ketogenesis”—is essential to prevent liver injury due to a high-fat diet. While the gene was nonessential in mice fed a normal, low-fat diet, mice fed a high-fat diet developed severe liver injuries when they lacked the function of the gene—and this seemed to be due to the inability of liver mitochondria to perform normal ketogenesis. Using chemical techniques to study the metabolites produced in these “ketogenesis insufficient” mice, the problem was linked to low levels of an essential metabolite (Coenzyme A).
Linking the problem to a specific molecular deficiency, the researchers then artificially raised levels of Coenzyme A in sick, high-fat fed mice by infusing precursor molecules directly into the liver—and they found that supplementation alone was able to rescue normal liver function. The ability of specific metabolites to rescue fat induced liver injury, and the connection of liver injury to a specific genetic deficiency raises the possibility that further research will find either oral supplements or dietary modifications that can help counteract these kind of liver injuries in humans.