Bezafibrate Mildly Stimulates Ketogenesis and Fatty Acid Metabolism in Hypertriglyceridemic Subjects

Abstract

Our objective was to determine whether bezafibrate, a hypotriglyceridemic drug and peroxisome proliferatoractivated receptor (PPAR)-␣ agonist, is ketogenic and increases fatty acid oxidation in humans. We measured fatty acid metabolism and ketone levels in 13 mildly hypertriglycemic adults (67 Ϯ 11 years old) during 2 metabolic study days lasting 6 h, 1 day before and 1 day after bezafibrate (400 mg of bezafibrate per day for 12 weeks). ␤-Hydroxybutyrate, triglycerides, free fatty acids, fatty acid profiles, insulin, and glucose were measured in plasma, and fatty acid ␤-oxidation was measured in breath after an oral 50-mg dose of the fatty acid tracer [U-13 C]linoleic acid. As expected, 12weeks on bezafibrate decreased plasma triglycerides by 35%. Bezafibrate tended to raise postprandial ␤-hydroxybutyrate, an effect that was significant after normalization to the fasting baseline values (p ϭ 0.03). ␤-Oxidation of [U-13 C]linoleic acid increased by 30% (p ϭ 0.03) after treatment. On the metabolic study day after bezafibrate treatment, postprandial insulin decreased by 26% (p ϭ 0.01), and glucose concentrations were lower 2 to 5 h postprandially. Thus, in hypertriglyceridemic individuals, bezafibrate is mildly ketogenic and significantly changes fatty acid metabolism, effects that may be linked to PPAR␣ stimulation and to moderately improved glucose metabolism.As the population ages, the prevalence of cognitive impairment in the elderly, particularly Alzheimer's disease (AD), is increasing markedly. Glucose is the brain's main energy substrate, providing energy to make ATP to maintain ion gradients, synaptic transmission, protein synthesis (for review, see Hoyer, 1996), and fatty acid turnover in membranes phospholipids (Rapoport et al., 2001). A decline in cerebral glucose metabolism is widely reported in AD (Foster et al., 1984;Blennow et al., 2006;Mosconi et al., 2007). This deterioration in brain fuel supply is progressive, correlates broadly with dementia severity, and may appear during normal aging at which time there can be an approximately 6% reduction in glucose uptake per decade (Petit-Taboué et al., 1998). Reduced brain glucose metabolism can arise before the clinical symptoms of AD (Reiman et al., 2004) and may contribute to neurodegenerative processes leading to AD (Liu 2004(Liu , 2008. As such, an alternative brain fuel to glucose may be therapeutically useful in AD.Physiologically, ketone bodies [or ketones; ␤-hydroxybutyrate (␤-OHB), acetoacetate, and acetone] are the main alternative energy substrate to glucose for brain metabolism and are especially important during periods of glucose deprivation. Ketones can supply up to two thirds of the energy requirement of the brain during starvation (Owen et al., 1967). Mildly increasing ketone synthesis has been proposed as a possible therapeutic approach to correct or bypass brain

Comparison of the pharmacological profiles of murine antisense oligonucleotides targeting apolipoprotein B and microsomal triglyceride transfer protein

“…Therefore, the differences in TG accumulation between apoB and MTP ASO treatment appear to be due in part to 1 ) the inability of MTP ASO-treated animals after long-term treatment to suppress lipogenesis, 2 ) the development of larger lipid droplets with the MTP ASO, and 3 ) reduced PPAR ␥ AMPK ␣ mRNA levels were increased after apoB ASO treatment ( Table 5 ). An established method to detect hepatic ␤ oxidation is to evaluate 3HB, or ketone levels, in vivo (32,33). Using that technique, it appeared that 3HB was increased in apoB ASO-treated DIO mice after 2 weeks of treatment ( Table 1 ), when liver TG levels were elevated in comparison to controls ( Table 3 ), but after 6 weeks, when hepatic TG levels were similar to controls, 3HB levels returned to those observed in control ASO-treated mice.…”

Peroxisome Proliferator Activated Receptor Alpha (PPAR) Agonists: A Potential Tool for a Healthy Aging Brain

“…Fibrate therapy reduces the incidence and delays the onset of type II diabetes and seems to improve insulin sensibility in humans (Goldenberg et al, 2008). A recent clinical study suggests that in hypertriglyceridemic individuals, bezafibrate increase the production of ketone bodies, the alternative energy source for the brain (Tremblay-Mercier et al, 2010). Thus, by reducing triglycerides, enhancing glucose availability, providing alternative brain fuel and improving cardiovascular profile, PPAR agonist could have relevant impact on the maintenance of a good cognitive health later in life (figure 8).…”

“…However, there is not a clear consensus regarding the direct impact of fibrate on insulin sensibility, but from studies reviewed, 10 showed an improvement (Tenenbaum et al, 2007, Cree et al, 2007, Kim et al, 2003, Damci et al, 2003, Jonkers et al, 2001, Idzio-Wallus, 2001, Yong et al, 1999, Kobayashi et al, 1988, Murakami et al 1984, Ferrari et al, 1977 and 6 a reduction in sensibility or no change (Anderlova et al, 2007, Rizos et al, 2002, Whitelaw et al, 2002, Asplund-Carlson, 1996, Sane et al, 1995, Skrha et al, 1994 . In a recent study (2010) bezafibrate treatment for 12 weeks in a mild hypertriglyceridemic population showed a postprandial insulin response 26% lower after bezafibrate, suggesting the beneficial impact of fibrate on insulin sensitivity (figure 4; Tremblay-Mercier et al, 2010). Further clinical studies measuring insulin sensibility are warranted to confirm the real insulin-sensitizing potential of fibrates and the subsequent impact on brain glucose metabolism and further impact on cognition.…”

“…This study suggests that treatment with bezafibrate has a mild ketogenic potential; postprandial -OHB response was 58% higher after bezafibrate treatment for 12 weeks. With bezafibrate treatment, the level of ketones ( -OHB) was low during fasting (early in the morning) but was rising during the experimental day to reach 0.3-0.4 mM -OHB at the end of the day (Tremblay-Mercier et al, 2010). Perhaps in conjunction with a fibrate, joint administration of a dose of MCT, would maintain a moderate level of circulating ketones to insure the delivery to the brain to maintain the energetic homeostasis (Tremblay-Mercier et al, 2010).…”

“…With bezafibrate treatment, the level of ketones ( -OHB) was low during fasting (early in the morning) but was rising during the experimental day to reach 0.3-0.4 mM -OHB at the end of the day (Tremblay-Mercier et al, 2010). Perhaps in conjunction with a fibrate, joint administration of a dose of MCT, would maintain a moderate level of circulating ketones to insure the delivery to the brain to maintain the energetic homeostasis (Tremblay-Mercier et al, 2010). Preliminary results concerning cerebral ketone metabolism with the tracer 11 Cacetoacetate shows that brain ketones uptake is proportional to physiologic plasma ketones concentration as expected by anterior studies ).…”